After Saint and Holmgren were diagnosed as HIV-positive, Saint threw himself into AIDS activism. He was aware of too many artists who went to their deaths in secrecy about their AIDS status and determined that he would be open about his struggle. He was one of five AIDS activists featured in Marlon Riggs' film No Regrets (Non, Je Regrette Rien) (1993).

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Published at a time when the American government was still reluctant to fund AIDS research and prevention programs, Saint's collections of poems Stations and Wishing for Wings celebrated the solidarity among gay men in the face of the disease and contrasted this type of queer heroism with the indifference of politicians and decision-makers.

Saint conceived his work as a challenge to the social norms that required invisibility and silence from both black gay men and people with AIDS. His writing constantly reverses expectations regarding sex and gender and provocatively combines queerness and traditional Haitian folklore and mythology.

The artist never relinquished his Haitian cultural heritage. In spite of the widespread in the Haitian diasporic community, Saint felt linked to that community because of their common fights against the oppressive regime of the Haitian dictator Jean-Claude "Baby Doc" Duvalier.

In addition to retaining close connections to his home country, Saint also fully participated in the social and political movements in the United States, demanding more effective measures against racial and sexual discrimination, and participating in demonstrations and protests against the government's ineffective response to the AIDS crisis.

Saint's work is motivated by the conviction that the personal is the political; as the author himself wrote in Spells of a Voodoo Doll: "[o]ur writings should very much be a public process that reflects private passions." His poetry starts from private and personal passions to confront the AIDS crisis openly, thus conceiving poetic composition as an act of survival that breaks the silence surrounding people with AIDS even as it also disturbingly documents the physical and psychological ravages of the disease.

The death of Holmgren on March 29, 1993 profoundly affected Saint. In the three-part prose piece entitled "No More Metaphors" interwoven through the poems in Wishing for Wings, the writer concludes that no words can convey his despair over the death of his partner. However, as with most of Assotto's oeuvre, "No More Metaphors" can be easily reversed in meaning and be read, rather than simply an admission of despair, as a call to political activism, encouraging his readers to confront the virus in all its aspects, including the most devastating ones.

Assotto Saint died of AIDS-related complications on June 29, 1994. In the preface to the anthology The Road before Us, Saint had requested that, in protest of the indifference of American society to those dying of AIDS, that the American flag be burned at his funeral and its ashes scattered on his grave.

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