Stiers was born in Peoria, Illinois. He began his acting career in northern California and later moved to New York City, where he joined John Houseman's The Acting Company.

Stiers joined the cast of M*A*S*H in 1977. His character was not a replacement of Larry Linville's character, Frank Burns, but a completely different foil for Hawkeye Pierce and B.J. Hunnicutt. He appeared in M*A*S*H until the end of the series. Later, Stiers provided his voice to many Disney features: as the voice of Cogsworth in Beauty and the Beast (1991), a dual role as Sir John Ratcliffe and his lackey Wiggins in Pocahontas, as the Archdeacon in Hunchback of Notre Dame (1996), and as the voice of Dr. Jumba Jookiba in Lilo & Stitch (2002). He was also the voice of Nicky Flippers in the 2005 release of Hoodwinked. He played a Congressman in the North and South miniseries with Patrick Swayze and the amiable mayor of Grady opposite Michael J. Fox in Doc Hollywood. Many would also recognize him as John Cusack's flustered father in the cult movie, Better Off Dead.

He voiced the character of Mr Jolly in Disney's Teacher's Pet TV series (2000 to 2002), and the subsequent feature film by the same name.

In 1999, he was cast in the short-lived CBS comedy Love and Money as Nicholas Conklin, a belligerent billionaire whose personality was similar to that of M*A*S*H's Major Winchester.

In 2001, he was the voice of Kamaji in the English-language version of the Academy Award winning film, Hayao Miyazaki's Spirited Away.

In 2003 Stiers made a cameo appearance on the critically acclaimed CBS series Touched by an Angel. He portrayed Satan in the personification of a lawyer.

Additional voice work has included narration for various episodes of PBS's Nova science program.

He also guest starred in the Star Trek: The Next Generation episode "Half a Life", the Matlock episode "The Ambassador" and in an ALF episode. As of 2002, he is a regular in the television series The Dead Zone.

After a minor voice role in the computer game Uru: Ages Beyond Myst, Stiers took on the new role of Esher in its successor, Myst V: End of Ages. Stiers played the voice and face of Esher, and his face was mapped onto the 3D character.

Was the voice of the Narrator in the computer game Icewind Dale, released in 2000.

In addition to acting he is a professional musician, and has served as music director and principal guest conductor of many orchestras.

He is sometimes credited as 'David Stiers', 'David Odgen Stires', and 'David Ogden Steers'.

In 2006, he reprised the role as Cogsworth in the Square-Enix/Disney video game Kingdom Hearts II.