It is summer of 1981. Ned Weeks (Mark Ruffalo) is an openly gay writer from New York City who travels to Fire Island Pines on Long Island to celebrate the birthday of his friend Craig Donner (Jonathan Groff) at a house on the beach. Other friends in attendance include Mickey Marcus (Joe Mantello) and the charismatic Bruce Niles (Taylor Kitsch), who has recently begun dating Craig. Craig is young and appears to be in good health. While walking on the beach, however, Craig feels dizzy and collapses. Later, when blowing out the candles on his birthday cake, Craig begins to cough repeatedly.
While traveling back to New York City, Ned reads an article in The New York Times titled "Rare Cancer Diagnosed in 41 Homosexuals." Back in the city, he visits the offices of Dr. Emma Brookner (Julia Roberts), a physician who has seen many patients unexpectedly afflicted with the symptoms of rare diseases that normally wouldn't harm people unless their immune systems have been compromised. All of these cases seem to be appearing in gay men. In the waiting room, Ned meets Sanford (Stephen Spinella), a patient whose face and hands are marked with skin lesions caused by Kaposi's sarcoma, a rare cancer. Brookner examines Ned, but finds that he does not have the symptoms of this disease. She asks Ned to help her raise awareness of this disease within the gay community.
Craig suddenly suffers violent convulsions and is rushed to the hospital with Ned, Mickey, and Bruce where he is later pronounced dead. Brookner recognizes Bruce, noting that he is the former boyfriend of another one of her patients who recently died. Ned organizes a gathering at his home where many local gay men are invited to hear Brookner share information about the disease. Though she lacks conclusive evidence, she states her belief that the illness is sexually transmissible and that they should all avoid having sex for the time being to prevent new transmissions. Most attendees question her belief. She notes that few medical journals appear interested in publishing anything on this disease which is mostly affecting homosexual men. Ned announces that he wants to start an organization to spread information about the disease and provide services to those who have been infected.
Brookner and Ned visit a local hospital where several of her sick patients are in critical condition with an illness that is now being referred to as gay-related immune deficiency (GRID). They stay in rooms that many hospital staff are afraid to enter for fear of contracting the disease. Ned, Bruce, Mickey, and several other friends including Tommy Boatwright (Jim Parsons) establish a community organization called Gay Men's Health Crisis (GMHC). The organization sponsors fundraisers for research on the disease now called AIDS and establishes a telephone hotline, counseling, and other services. Over Ned's objections, they elect Bruce their President. Ned arranges for his older brother, lawyer Ben Weeks (Alfred Molina), to provide free legal advice to the GMHC. The two brothers are close, but there remains an underlying tension over Ben's lack of understanding of Ned's sexuality. Ned contacts gay New York Times reporter Felix Turner (Matt Bomer), hoping that he can use his media connections to publish more stories about the unfolding health crisis. Felix laments that it's difficult getting any mainstream newspapers to report much information on AIDS. The two begin a romantic relationship.
The disease continues to spread and claim lives. Bruce attempts to travel to Phoenix with his boyfriend Albert (Finn Wittrock), who is dying, so that Albert can see his mother one more time. The airline refuses at first to fly the plane with sick Albert on board. When they do eventually get to Phoenix, Albert dies following a period of dementia. The hospital doctors refuse to examine him and issue a death certificate, and instead throw him out with the garbage while Bruce bribes a funeral home to cremate his body without a death certificate. Brookner attempts to obtain grant money to continue researching AIDS, but her efforts are rejected by government officials who do not see AIDS as a priority. Ned, meanwhile, is kicked out of GMHC for his combative and aggressive tactics to promote awareness of AIDS, which is causing tension within the group.
Felix comes down with symptoms and his body wastes away as the disease claims his life. Felix arranges for a will with the help of Ben, and leaves everything he has to Ned. The two state their love for one another at the hospital before Felix dies. A few days later, Ned visits his alma mater, Yale University, where a Gay Week is being hosted by the students. He admires how young men and women are able to dance with one another openly, without fear of discrimination.
Information is displayed about the growing number of people contracting AIDS, as Tommy's Rolodex pile (the contact info of his friends who have died from AIDS) grows bigger, eventually including Bruce Niles.