Originally named Asylum for the Insane, it was the first institution organized by a group of prominent Bostonians who were concerned about homeless mentally ill persons "abounding on the streets and by-ways in and about Boston".

Joseph Curtis (civil engineer) and Frederick Law Olmsted (the renowned landscape architect who also conceptualized the Emerald Necklace public spaces of Boston, New York's Central Park, and Hartford's Institute of Living) were consulted on the selection of the hospital site.

[3] In the 1990s, facing falling revenue in a changing health care industry, the hospital drafted a plan to sell a portion of its grounds for development in the Town of Belmont.

[5][6] As of 2020[update], McLean is led by Scott L. Rauch,[7] President and Psychiatrist in Chief, who is known for his innovative work using brain imaging methods to study psychiatric dysfunction.

[9][10][11] Mathematician John Nash;[14][15] musicians James Taylor,[16][17] and Ray Charles;[16][18] poets Sylvia Plath, Robert Lowell and Anne Sexton; Massachusetts politician and Civil War general Nathaniel P. Banks; authors Susanna Kaysen[16][17] and David Foster Wallace;[19][20] and criminal Michelle Carter have been treated at McLean Hospital.

[22] One popular and anecdotal history of McLean is Alex Beam's Gracefully Insane: Life and Death Inside America's Premier Mental Hospital.

Memoirs of time spent within McLean's walls include Sylvia Plath's novel The Bell Jar, and Susanna Kaysen's Girl, Interrupted, which was made into a film of the same name starring Winona Ryder and Angelina Jolie.

Samuel Shem's roman à clef Mount Misery tells a story inspired at least in part by the author's experiences at McLean.