He established himself early as a Juilliard-trained stage actor before portraying Superman/Kal-El/Clark Kent in four films, from 1978 to 1987. In the 1980s, he starred in several films, including Somewhere in Time (1980), Deathtrap (1982), The Bostonians (1984), and Street Smart (1987). He also starred in many plays, including the Broadway plays Fifth of July (1980 - 1982) and The Marriage of Figaro (1985). In 1987, he led a public rally in support of 77 Chilean actors, directors, and playwrights who had been sentenced to death by the dictator Pinochet for criticizing his regime in their works. Pinochet canceled the sentence after the ensuing media coverage, and Reeve was awarded with three national distinctions from Chile for his actions. In the 1990s, Reeve acted in such films as Noises Off (1992), The Remains of the Day (1993), and Village of the Damned (1995).

In May 1995, Reeve was paralyzed in an accident while competing in an equestrian tournament, and used a wheelchair for the rest of his life. He lobbied for people with spinal cord injuries, and for human embryonic stem cell research. He founded the Christopher Reeve Foundation and co-founded the Reeve-Irvine Research Center. Reeve died at age 52 on October 10, 2004 from cardiac arrest caused by an adverse reaction to antibiotics given for a systemic infection. There are two movies and a TV series episode dedicated to his memory: Superman II: The Richard Donner Cut and Superman Returns, both made in 2006; and the episode Devoted from Season 4 of Smallville which aired in 2004.

Reeve married Dana Morosini in April 1992, and they had a son, Will. Reeve also had two children, Matthew and Alexandra, from a previous relationship with Gae Exton. Dana Reeve died of lung cancer in March 2006. Superman Returns is also dedicated to Dana Reeve.