At the age of eleven Chalmers was entered as a student at St Andrews, where he devoted himself almost exclusively to mathematics. In January 1799 he was licensed as a preacher of the Gospel by the St Andrews presbytery. In May 1803, after attending further courses of lectures in The University of Edinburgh, and acting as assistant to the professor of mathematics at St Andrews, he was ordained as minister of Kilmany, about 9 miles from the university town, where he continued to lecture. He was highly regarded during his lifetime as a natural theologian.

His mathematical lectures roused so much enthusiasm that they were discontinued by order of the authorities, who disliked the disturbance of the university routine which they involved. Chalmers then opened mathematical classes on his own account which attracted many students; at the same time he delivered a course of lectures on chemistry, and ministered to his parish at Kilmany. In 1805 he became a candidate for the vacant professorship of mathematics at The University of Edinburgh, but was unsuccessful. In 1808 he published an Inquiry into the Extent and Stability of National Resources, a contribution to the discussion created by Bonaparte's commercial policy. Domestic bereavements and a severe illness then turned his thoughts in another direction.

At his own request the article on Christianity was assigned to him in Dr Brewster's Edinburgh Encyclopaedia, and in studying the credentials of Christianity he received a new impression of its contents. His journal and letters show how he was led from a sustained effort to attain the morality of the Gospel to a profound spiritual revolution. After this his ministry was marked by a zeal which made it famous. The separate publication of his article in the Edinburgh Encyclopaedia, and contributions to the Edinburgh Christian Instructor and The Eclectic Review, enhanced his reputation as an author. In 1815 he became minister of the Tron Church, Glasgow, in spite of determined opposition to him in the town council on the grounds of his evangelical teaching. From Glasgow his repute as a preacher spread throughout the United Kingdom. A series of sermons on the relation between the discoveries of astronomy and the Christian revelation was published in January 1817, and within a year nine editions and 20,000 copies were in circulation. When he visited London Wilberforce wrote, "all the world is wild about Dr Chalmers."

In Glasgow Chalmers made one of his greatest contributions to the life of his own time by his experiments in parochial organization. His parish contained about 11,000 persons, and of these about one-third were unconnected with any church. He diagnosed this evil as being due to several shortages: personal influence; spiritual oversight; and the raw number of parochial organizations, which had not kept pace in the city, as they had done in rural parishes, with the growing population. He declared that twenty new churches, with parishes, should be erected in Glasgow, and he set to work to revivify, remodel and extend the old parochial economy of Scotland. The town council consented to build one new church, attaching to it a parish of 10,000 persons, mostly weavers, labourers and factory workers, and this church was offered to Dr Chalmers that he might have a fair opportunity of testing his system.

In September 1819 he became minister of the church and parish of St John, where of 2000 families more than 800 had no connection with any Christian church. He first addressed himself to providing schools for the children. Two school-houses with four endowed teachers were established, where 700 children were taught at the moderate fees of 2 and 3 shillings per quarter. Between 40 and 50 local Sabbath schools were opened, where more than 1000 children were taught the elements of secular and religious education. The parish was divided into 25 districts embracing from 60 to 100 families, over each of which an elder and a deacon were placed, the former taking oversight of their spiritual, the latter of their physical needs. Chalmers was the mainspring of the whole system, not merely superintending the visitation, but personally visiting all the families, and holding evening meetings, when he addressed those whom he had visited.

This parochial machinery enabled him to make a singularly successful experiment in dealing with the problem of poverty. At this time there were not more than 20 parishes north of the Forth and Clyde where there was a compulsory assessment for the poor, but the English method of assessment was rapidly spreading. Chalmers believed that compulsory assessment actually swelled the evil it was intended to mitigate, and that relief should instead be raised and administered by voluntary means. His critics replied that this was impossible in large cities. When he undertook the management of the parish of St John's, the poor of the parish cost the city £1400 per annum, and in four years, by the adoption of his method, the pauper expenditure was reduced to £280 per annum. The investigation of all new applications for relief was committed to the deacon of the district, and every effort was made to enable the poor to help themselves. When once the system was in operation it was found that a deacon, by spending an hour a week among the families committed to his charge, could keep himself acquainted with their character and condition.

In 1823, after eight years of work at high pressure, he was glad to accept the chair of moral philosophy at St Andrews University, the seventh academic offer made to him during his eight years in Glasgow. In his lectures he excluded mental philosophy and included the whole sphere of moral obligation, dealing with man's duty to God and to his fellow-men in the light of Christian teaching. Many of his lectures are printed in the first and second volumes of his published works. In the field of ethics he made contributions in regard to the place and functions of volition and attention, the separate and underived character of the moral sentiments, and the distinction between the virtues of perfect and imperfect obligation. His lectures kindled the religious spirit among his students, and led some of them to devote themselves to missionary effort. In November 1828 he was transferred to the chair of theology in Edinburgh. He then introduced the practice of following the lecture with a viva voce examination on what had been delivered. He also introduced text-books, and came into stimulating contact with his people; perhaps no one has ever succeeded as he did by the use of these methods in communicating intellectual, moral and religious impulse to so many students.

In 1841 the movement which ended in the Disruption was rapidly culminating, and Dr Chalmers found himself at the head of the party which stood for the principle that no minister shall be intruded into any parish contrary to the will of the congregation. Cases of conflict between the church and the civil power arose in Auchterarder, Dunkeld and Marnoch, and when the courts made it clear that the church, in their opinion, held its temporalities on condition of rendering such obedience as the courts required, the church appealed to the government for relief. In January 1843 the government put a final and peremptory negative on the church's claims for spiritual independence.

On 18 May 1843, 470 clergymen withdrew from the general assembly and constituted themselves the Free Church of Scotland, with Dr Chalmers as moderator. He had prepared a sustentation fund scheme for the support of the seceding ministers, and this was at once put into successful operation.On 28 May of last-mentioned year he returned to his house at Morningside, near Edinburgh, from a journey to London on the subject of national education. On the following day (Saturday) he was busily employed in preparing a report to the General Assembly of the Free Church, then sitting. On Sunday, the 30th, he continued in his usual health and spirits, and retired to rest with the intention of rising at an early hour to finish his report. The next morning he did not make his appearance, and no answer being returned on knocking, his room was entered, and he was discovered lying tranquilly in bed quite dead. He had evidently died in a moment, without pain or even consciousness. He was interred in the Grange Cemetery, whither an immense assemblage of persons of all denominations accompanied his remains to the grave. (reference from The Popular Encyclopedia; or, Conversations Lexicon, published by Blackie & Son, 1883.)

Dr Chalmers's action throughout the Free Church controversy was so consistent in its application of Christian principle and so free from personal or party animus, that his writings are a valuable source for argument and illustration on the question of Establishment. "I have no veneration", he said to the royal commissioners in St Andrews, before either the voluntary or the non-intrusive controversies had arisen, "for the Church of Scotland qua an establishment, but I have the utmost veneration for it qua an instrument of Christian good." He was transparent in character, chivalrous, kindly, firm, eloquent and sagacious; his purity of motive and unselfishness commanded absolute confidence; he had originality and initiative in dealing with new and difficult circumstances, and great aptitude for business details.

During a life of incessant activity Chalmers scarcely ever allowed a day to pass without its modicum of composition; at the most unseasonable times, and in the most unlikely places, he would occupy himself with literary work. His writings occupy more than 30 volumes. He would have stood higher as an author had he written less, or had he indulged less in that practice of reiteration into which he was constantly betrayed by his anxiety to impress his ideas upon others. As a political economist he was the first to unfold the connection that subsists between the degree of the fertility of the soil and the social condition of a community, the rapid manner in which capital is reproduced (see Mill's Political Economy, i. 94), and the general doctrine of a limit to all the modes by which national wealth may accumulate. He was the first also to advance that argument in favour of religious establishments which meets upon its own ground the doctrine of Adam Smith, that religion like other things should be left to the operation of the natural law of supply and demand.

His academic years were prolific also in literature of various kinds. In 1826 he published a third volume of the Christian and Civic Economy of Large Towns, a continuation of work begun at St Johns, Glasgow. In 1832 he published a Political Economy, the chief purpose of which was to enforce the truth that the right economic condition of the masses is dependent on their right moral condition, that character is the parent of comfort, not vice versa. In 1834 Dr Chalmers was elected fellow of the Royal Society of Edinburgh, and in the same year he became corresponding member of the Institute of France; in 1835 Oxford conferred on him the degree of D.C.L. In 1834 he became leader of the evangelical section of the Scottish Church in the General Assembly. He was appointed chairman of a committee for church extension, and in that capacity made a tour through a large part of Scotland, addressing presbyteries and holding public meetings. He also issued numerous appeals, with the result that in 1841, when he resigned his office as convener of the church extension committee, he was able to announce that in seven years upwards of 300,000 had been contributed, and 220 new churches had been built. His efforts to induce the Whig government to assist in this effort were unsuccessful.

Chalmers' Bridgewater Treatise, in the series On the Power, Wisdom and Goodness of God as Manifested in the Adaptation of External Nature to the Moral and Intellectual Constitution of Man, appeared in two volumes 1833 and went through 6 editions. As noted by Robert M. Young, these books effectively represent an encyclopedia of pre-evolutionary natural history, commissioned and published whilst Charles Darwin was on board The Beagle.

In the department of natural theology and the Christian evidences he ably advocated that method of reconciling the Mosaic narrative with the indefinite antiquity of the globe which William Buckland (1784-1856) advanced in his Bridgewater Treatises, and which Dr. Chalmers had previously communicated to him. His refutation of David Hume's objection to the truth of miracles is perhaps his intellectual chef d'oeuvre. The distinction between the laws and dispositions of matter, as between the ethics and objects of theology, he was the first to indicate and enforce, and he laid great emphasis on the superior authority as witnesses for the truth of Revelation of the Scriptural as compared with the Extra-Scriptural writers, and of the Christian as compared with the Christian testimonies. In his Institutes of Theology, no material modification is attempted on the doctrines of Calvinism, which he received with all simplicity of faith as revealed in the Divine word, and defended as in harmony with the most profound philosophy of human nature and of the Divine providence.