He will join Matthew McConaughey and Gael Garcia Bernal in Jean-Marc Vallee's drama, reports Variety.
Based on a true story, the film centres around Texan electrician Ron Woodroof (McConaughey), who survived for six years after developing Aids in 1986, when he was told he would only live for six months.
Unwilling to accept the death sentence and frustrated by the lack of healthcare options, he set up a smuggling operation, making alternative medicines available to Aids patients.
Leto will play another HIV positive man who meets Woodroof in hospital.
Jessica Garner is reportedly in line for the role of Dr Eve Saks.
Leto, who is the frontman of band 30 Seconds to Mars, was last seen in 2009's Mr Nobody.
Shooting on The Dallas Buyers Club is scheduled to begin in November in New Orleans.