Todd was born Mabel Loomis in Cambridge, Massachusetts. She graduated from Georgetown Seminary in Washington, D.C., then studied music at the New England Conservatory in Boston.

On March 5, 1879, she married astronomer David Peck Todd, with whom she had one daughter, Millicent. Mabel Loomis Todd had a passionate sexual nature and wrote freely about it. She wrote soon after her marriage: "Sweet communions. Oh joy! Oh! Bliss unutterable" and "A little Heaven just after dinner." In May 1879, the day she got pregnant, she noted: "A very happy few minutes of love in our room."

She later had an affair with Austin Dickinson, the (married) brother of Emily. According to Peter Gay's distinguished book, as reviewed in Time Magazine of January 23, 1984,Todd kissed Austin Dickinson after he had died, kissed "the dear body, every inch of which I know and love so utterly." As described by Lyndall Gordon, the affair...romanticized by Todd descendants...actually devastated Sue Dickinson, the wife of Austin, and impacted the writing of Emily, who is said to have had to witness audibly the ongoing affair, and to have been routinely displaced from her place of creative work to provide it an ongoing venue.

Mabel Todd never met Emily Dickinson in person, and though the two women exchanged letters, it has been said that "Mabel effectively destroyed the Dickinson family". After Emily's death in 1886, hundreds of her unpublished poems were discovered and Todd took to herself the task, with Dickinson family consent, to copy and organize the poems. The first volume of Poems by Emily Dickinson was published in 1890, and included many alterations by Todd "that suppressed some of their originality".

In 1896, Todd and the Dickinson family had a falling-out over a legal battle regarding property owned by Austin Dickinson. As a result, Emily Dickinson's manuscripts were split between the two families. In 1945, Todd's daughter Millicent published some of the poems from Todd's portion of the manuscripts.

Todd was a member of the Audubon Society.

Mabel Loomis Todd died in Hog Island, Maine.