Born in Belfast in 1754, William was son to Reverend Thomas Drennan (1696-1768), minister of Belfast's First Presbyterian Church. Thomas Drennan was an educated man from the University of Glasgow and was ordained to the congregation of Holywood, county Down in 1731. Drennan was heavily influenced by his father, whose religious convictions served as the foundation for his own radical political ideas.

In 1769 he followed in his father's footsteps by enrolling in the University of Glasgow where he became interested in the study of philosophy. In 1772 he graduated in arts and then in 1773 he commenced the study of medicine at Edinburgh. After graduating in 1778 he set up practice in Belfast, specialising in obstetrics. He is credited with having been one of the earliest advocates of inoculation against smallpox, and of hand washing to prevent the spread of infection. Drennan also wrote much poetry, coining the phrase "Emerald Isle" and was the founder and editor of a literary periodical, "Belfast Magazine". He moved to Newry in 1783 but eventually moved to Dublin in 1789 where he quickly became involved in nationalist circles.

Like many other Ulster Presbyterians, William was an early supporter of the American Colonies in the American Revolution and joined the Volunteers who had been formed to defend Ireland for Britain in the event of French invasion. The Volunteer movement soon became a powerful political force and a forum for Protestant nationalists to press for political reform in Ireland eventually assisting Henry Grattan to achieve home rule in 1782. However Drennan, like many other reformers, quickly became dismayed by the conservative and sectarian nature of the Irish parliament and in 1791 he co-founded the Society of United Irishmen with Wolfe Tone and Thomas Russell.

He wrote many political pamphlets for the United Irishmen and was arrested 1794 for seditious libel, a political charge that was a major factor in driving the United Irishmen underground and into becoming a radical revolutionary party. Although he was eventually acquitted, he gradually withdrew from the United Irishmen though he continued to campaign for Catholic emancipation.

He settled in Belfast in 1807 after inheriting a large fortune and in 1810 was a co-founder of the non-denominational Royal Belfast Academical Institution. As a poet, he is best remembered for his poem The Wake of William Orr, written in memory of the executed United Irishman, who was widely regarded as a martyr at the time. Some of its most famous lines went;

" Here our murdered brother lies,

Wake him not with women's cries;

Mourn the way that manhood ought,

Sit in silent trance of thought.. "

He died in 1820 and showed his non-sectarian outlook was unchanged by stipulating that his coffin be carried by an equal number of Catholics and Protestants with clergy from different denominations in attendance.

In November 2007, the William Drennan Cumann of Queens University Belfast, was founded to support the newly established Fianna Fáil society in the university. It was officially welcomed into the Fianna Fáil on 7 December 2007 by then Taoiseach Bertie Ahern and leader of Fianna Fáil.