Cyphers' roles on the stage, both on- and off-Broadway, include 12 Angry Men, in which he portrayed "Juror #3" to Julie Cobb's "#2" (her father portrayed "#3" in the 1957 movie). Cyphers appeared on The Dating Game in 1967 to compete for a date with Yvonne Craig ("Batgirl" from the 1960s Batman TV series).

Cyphers has appeared in numerous television productions. During the 1970s, he had a recurring role, as Hugo Muncy, in The Betty White Show, and he guest-starred in an episode of Gibbsville in 1976. In addition, he had guest roles in popular television series such as Barnaby Jones and The Dukes of Hazzard, and he played Drake in the 1977 mini series Roots.

Cyphers's first feature film was the 1974 movie Truck Turner, and he first worked with Carpenter in the 1976 action film Assault on Precinct 13, in which he played Starker, one of the ill-fated police officers gunned down by gang members.

After appearing in Halloween in 1978, Cyphers worked with Carpenter two years later, playing Dan O'Bannon in The Fog, a 1980 horror film which also starred Tom Atkins, Cyphers's fellow Halloween cast member Jamie Lee Curtis, his Assault on Precinct 13 co-star Darwin Joston, and Nancy Kyes, who worked with Cyphers in both Assault on Precinct 13 and Halloween. He then played the Secretary of State in Carpenter's popular 1981 film Escape from New York, in which he appeared with Atkins and Halloween Actress Nancy Stephens.

More recently, he has appeared in Sliders, ER, Seinfeld, JAG, and Any Day Now. From 1996 to 1998, Cyphers played Al Yaroker in the 1990s series Nick Freno: Licensed Teacher. He has also acted in various made-for-television movies.

In 2005, he appeared in the movie Dead Calling, and in 2007 he appeared as a Sheriff in Ethan Dettenmaier's forthcoming film, Sin-Jin Smyth, and in the film Methodic in a role which paid homage to his character in Halloween.