Distinctive and memorable characters that Paxton has played include the sneering older brother Chet in John Hughes' Weird Science; Hudson, the loud-mouthed space soldier in James Cameron's Aliens ("Game over, man! Game over!"); astronaut Fred Haise in Ron Howard's Apollo 13; the sadistic vampire Severen in Kathryn Bigelow's film Near Dark; and a tornado researcher opposite Helen Hunt in the blockbuster Twister.

Paxton moved to Los Angeles at 18 and began working for director Roger Corman as a set designer on his films. Exposed to films and actors at that age, had influenced his decision to pursue acting, and Paxton relocated to New York City where he studied with Lee Dittrich and Rob Morley.

In addition to his acting career, Paxton has directed a number of short films, including Fish Heads, which made a splash on Saturday Night Live in 1982. He has also moved into directing feature films with Frailty and The Greatest Game Ever Played. He was also a member of the band Martini Ranch.

He is currently seen in the television drama, Big Love, as the head of a polygynous family in Utah, produced by HBO.

Paxton claims the unusual distinction of being the only actor to be killed, on-screen, once each by an Alien, a Predator and a Terminator.