Also an environmental activist, Zuniga was a founding member of the Earth Communications Office (ECO), and has worked with the Natural Resources Defense Council, the Waterkeeper Alliance, and Environment California.
Zuniga was born in San Francisco, California to Agnes A. Zuniga (née Janawicz) and Joaquin Alberto Zuniga Mazariegos. Her mother is a Unitarian minister, of Polish and Finnish descent, and her father, originally from Guatemala, was an emeritus professor of philosophy at California State University, East Bay. Zuniga has two sisters: Jennifer Zuniga, and Rosario Zuñiga.
In her early teens, Zuniga expressed interest in acting, and attended the Young Conservatory program of the American Conservatory Theater of San Francisco. After her parents divorced, Zuniga moved with her mother and sister from Berkeley, California to Reading, Vermont, where she spent the remainder of her teenage years. Zuniga graduated from Woodstock Union High School in Woodstock, Vermont, in 1980, after which she returned to California and enrolled at the University of California, Los Angeles to study theater arts. After leaving college, Zuniga was close friends and roommates with fellow actress Meg Ryan.
Zuniga made her film debut in Stephen Carpenter's slasher film The Dorm That Dripped Blood (1982), playing a supporting role as a college coed. Two years later, she made her lead debut in The Initiation, another college-themed slasher co-starring Vera Miles and Clu Gulager. "It was a great part," Zuniga recalled. "I got to play twins: a good sister and an evil sister. I got shot in the back on-screen. It was pretty heavy for a first role."
She then appeared in the drama Vision Quest (1985), followed by a lead role in Rob Reiner's The Sure Thing (1985), opposite John Cusack. The film was critically praised; critic Roger Ebert said of the film: "The movie industry seems better at teenage movies like Porky's, with its sleazy shower scenes, than with screenplays that involve any sort of thought about the love lives of its characters. That's why The Sure Thing is a small miracle." Shortly after, Zuniga was cast in the television drama film Stone Pillow (1985), playing a social worker in New York City who forms a bond with an elderly homeless woman, played by Lucille Ball. She also appeared in the comedy Modern Girls (1986), opposite Cynthia Gibb and Virginia Madsen.
In 1987, Zuniga was cast as Princess Vespa in Mel Brooks's cult comedy Spaceballs, opposite Rick Moranis, Bill Pullman, and John Candy. Though the film received mixed critical reception, it later garnered a cult following. The next year, Zuniga appeared in a lead role in the blockbuster horror film The Fly II (1988), followed by the comedy Staying Together (1989), and as a med student opposite Matthew Modine in the drama Gross Anatomy (1989).
In 1992, she was cast as Jo Reynolds in the Fox soap opera Melrose Place, and appeared on the show as a recurring character until 1996. The role garnered Zuniga major exposure to television audiences, though her television career had begun in the early eighties with a minor role on Family Ties (1984) as a girlfriend of Alex P. Keaton. She also appeared in the 1995 miniseries Degree of Guilt.
In 1994, Zuniga appeared in the release of a video for Bob Seger's previously released 1976 hit "Night Moves". In the video version of the song, she and a pre-Friends Matt LeBlanc are shown in a 1960s drive-in theater, where Zuniga as a dark, edgy young woman becomes a visual fascination for LeBlanc as a clean-cut young man. Later, Zuniga would work as a voice actors on the animated television series Stories from My Childhood (1998), and also had a lead role in the miniseries Pandora's Clock (1996), an action thriller filmed in Seattle, Washington.
In 2005, she was cast as Lynn Kerr on the ABC family series Beautiful People, and also had a recurring role in the series American Dreams. She also appeared in a recurring role as Victoria Davis on The CW series One Tree Hill between 2008 and 2012, appearing in over forty episodes. During this time, she appears in several made-for-television movies including Secret Lives (2005), The Obsession (2006), Christmas Do-Over (2006), Mail Order Bride (2008), and On Strike for Christmas (2010).
In 2007, Zuniga co-produced and co-directed (with Steven Latham) the documentary "The Future We Will Create: Inside the World of TED" — a look at the annual Technology, Entertainment and Design conference held in Monterey, California. She also starred in the scripted web series Novel Adventures, which premiered November 3, 2008 from CBS Interactive. In February and March 2008, Zuniga appeared onstage in a production of The Scene by Theresa Rebeck, at the San Francisco Playhouse.
Zuniga reprised her role as Princess Vespa from the 1987 film Spaceballs, by voice-over in the television spin-off Spaceballs: The Animated Series. She also reprised her role from Melrose Place in an updated version, but it was short-lived, as the series was cancelled after just one season in 2009-10. In 2013, Zuniga appeared as a postal worker in the Hallmark Channel series Signed, Sealed, Delivered, as well as the television film based on the series. The following year, She starred in the Hallmark Channel film A Family Thanksgiving.
In 2015, Zuniga appeared in a guest starring role in the VH1 scripted series Hindsight as Libby. In 2016, she was cast in a new TV movie for Hallmark Channel, When Duty Calls, with Judd Nelson and Daniella Monet.
In 2016, Daphne Zuniga stars on Search Engines. Those Left Behind and Heartbeats.
She just finished two movies, The Wrong Babysitter and Framed.
Her younger sister Jennifer Zuniga, also an actress, debuted in the film A Woman, Her Men, and Her Futon (1992). Zuniga attends private Buddhist meditation retreats to manage stress in her life.
In 2004, Zuniga suffered from mercury poisoning, which she attributed to overconsumption of fish. She said she had eaten sushi four times in the week prior to being taken to the emergency room and that her symptoms included weak memory, headaches, crying spells, skin rashes, and mild depression. After her diagnosis, Zuniga stopped consuming fish in addition to other meat.
Zuniga has supported several environmental campaigns. In 2009, she was appointed by Los Angeles Mayor Antonio Villaraigosa to the Board of Directors of the Los Angeles River Revitalization Corporation, a not-for-profit development corporation charged with catalyzing sustainable development along the Los Angeles River.
Zuniga was a founding member of the Earth Communications Office (ECO), and has worked with the Natural Resources Defense Council, the Waterkeeper Alliance, and Environment California. Zuniga has cited her family's camping trips to Yosemite National Park and Yellowstone as sparking her lifelong interest in the environment. "The planet does nothing but support us," she said in a 2007 interview, "and we are constantly committing crimes against nature."