In July 1985, promiscuous Dallas electrician and rodeo cowboy Ron Woodroof (Matthew McConaughey) is diagnosed with AIDS and given 30 days to live. As a heterosexual, he initially refuses to accept the diagnosis but remembers having unprotected sex with a woman who was an intravenous drug user a couple years prior. He is soon ostracized by family and friends who mistakenly assume he contracted AIDS from homosexual relations. He gets fired from his job, and is eventually evicted from his home. At the hospital, he is tended to by Dr. Eve Saks (Jennifer Garner), who tells him that they are testing a drug called zidovudine (AZT), an antiretroviral drug which is thought to prolong the life of AIDS patients—and is the only drug approved by the Food and Drug Administration (FDA) for testing on humans. Saks informs him that in the clinical trials, half the patients receive the drug and the other half a placebo, as this is the only way they can determine if the drug is working.
Woodroof bribes a hospital worker to get him AZT. As soon as he begins taking it, he finds his health deteriorating (exacerbated by his cocaine use). When he returns to the hospital, he meets Rayon (Jared Leto), a drug addicted, HIV-positive trans woman, to whom he is initially hostile. As his health worsens, he drives to a makeshift Mexican hospital to get more AZT. The facility is run by a Dr. Vass, who has had his American medical license revoked because aspects of his work with AIDS patients had violated US regulations. Vass tells Woodroof that the AZT is “poisonous” and “kills every cell it comes into contact with”. He instead prescribes a cocktail of drugs and nutritional supplements centered on ddC and the protein peptide T, which are not yet approved in the US. Three months later, Woodroof finds his health much improved. It occurs to him that he could make money by importing the drugs and selling them to other HIV-positive patients. Since the drugs alone are not illegal, he is able to get them over the border by masquerading as a priest and swearing that they are for personal use. Meanwhile, Saks also begins to notice the negative effects of AZT, but is told by her supervisor, Dr. Sevard, that it cannot be discontinued.
Over the next year, Woodroof begins selling the drugs on the street and at gay nightclubs. He comes back into contact with Rayon, with whom he reluctantly sets up business since she can bring in more customers. The pair establish the “Dallas Buyers Club”, charging $400 per month for membership, and it becomes extremely popular. He gradually begins to respect Rayon as a friend. When Woodroof has a heart attack caused by a recently acquired dose of interferon, Sevard learns of the club and the alternative medication. He is angry that it is interrupting his trial, while the FDA confiscates the interferon and threatens to have Woodroof arrested. Saks agrees that there are benefits to AIDS medicine buyers clubs (of which there are several around the country) but feels powerless to change anything. The processes that the FDA uses to research, test and approve drugs are seen as flawed and a part of the problem for AIDS patients. Saks and Woodroof strike up a friendship.
The FDA gets a warrant to raid the Buyers Club, but can ultimately do nothing but fine Woodroof. In 1987, the FDA changes its regulations, making any unapproved drug illegal. As the Club runs out of funds, Rayon, who is addicted to cocaine, begs her father for money and tells Woodroof that she has sold her life insurance policy to raise money. Woodroof travels to Mexico and gets more of the peptide T. Upon return, Ron finds out that Rayon has died after being taken to the hospital. Saks is also upset by her death, and is asked to resign when the hospital discovers she has been linking patients with the Buyers Club, having learned that AZT trials previously conducted in France had proven the drug ineffective. She refuses, and insists that she will have to be fired instead.
As time passes, Woodroof shows more compassion towards gay, lesbian, and transgender members of the club and making money becomes less of a concern; his priority is provision of the drugs. Peptide T gets increasingly difficult to acquire, and in late 1987 he files a lawsuit against the FDA. He seeks the legal right to take the protein, which has been confirmed as non-toxic but is still not approved. The judge is sympathetic toward him and admonishes the FDA, but lacks the power to do anything. As the film ends, on-screen text reveals that the FDA later allowed Woodroof to take peptide T for personal use and that he died of the disease’s effects in 1992, seven years later than his doctors initially predicted.