Zuniga is best known for playing Jo Reynolds in the 1990s TV series Melrose Place. However, her television career began nearly ten years earlier when she appeared in several episodes of Family Ties (1982-84) as a girlfriend of Alex P. Keaton. She also co-starred with Lucille Ball in the TV drama Stone Pillow in 1985 and was in the 1985 television miniseries Degrees of Guilt. She was also one of many voice actors for the animated television series Stories from My Childhood (1998). Zuniga also had a lead role in the TV mini-series Pandora's Clock (1996).
In 2004-2005, Zuniga also appeared in a recurring role in American Dreams. She was on the show Beautiful People on ABC Family in 2005-2006. In 2007, she starred in the fifth season premiere of the dramatic series Nip/Tuck.
She also starred in several made for television movies including Secret Lives (2005), The Obsession (2006), and Christmas Do-Over (2006). Most recently, Zuniga starred in the made for television movie Mail Order Bride which premiered on November 8, 2008 on the Hallmark Channel.
Since 2007, Daphne Zuniga is on the CW hit show One Tree Hill. She plays the cold-hearted mother Victoria Davis. Also, she is currently reprising the role as the voice of Princess Vespa in the animated spin-off of the 1987 cult classic Spaceballs called Spaceballs: The Animated Series.
Zuniga reprised her role in an updated version of Melrose Place, but it was short-lived as the series was cancelled after just one season in 2009-10.