Zane was born in Chicago to Thalia and William George Zane Sr.; both were professional actors and founders of a school for medical technicians.^[1][2] His parents are of Greek descent (from Chios through his mother and Mani through his father); and his family's original surname, "Zanetakos", was anglicized to "Zane" by his parents. He grew up in the Greek Orthodox faith.^[3][4][5] He has an older sister, Lisa Zane, who is an actress and singer.^[6]

After completing a year of school at The American School in Switzerland (TASIS), Zane graduated from Francis W. Parker School and attended Harand Camp of the Theater Arts in Elkhart Lake, Wisconsin.^{[citation needed]}

Zane's first two screen roles were in the science fiction films Back to the Future in 1985 and Critters in 1986, around the same time he appeared in the music videos for Sheena Easton's songs "Do It For Love" and "Magic of Love". In 1988, he played Tony Gambini alongside Jessica Fletcher in Murder, She Wrote: A Very Good Year for Murder. Zane also appeared in an episode of Matlock entitled "The Nurse". In 1989, he reprised his henchman role in Back to the Future Part II. Earlier that same year, Zane gained international recognition with the role of villain Hughie Warriner in the thriller Dead Calm, alongside Nicole Kidman and Sam Neill. He also starred in the NBC film The Case of the Hillside Stranglers (1989), and Adam Sandler's "no budget" debut Going Overboard (1989) which was not released to a wider audience until 1996.

Zane's first starring role was in a 1990 independent film, the low-budget science fiction thriller Megaville. In 1990, he also co-starred as the bombardier in the film Memphis Belle, a film version of a 1944 film about a World War II Boeing B-17 Flying Fortress bomber. Zane also forayed into television work, and in 1991 he appeared as John Justice Wheeler in several episodes of David Lynch's hit TV-series Twin Peaks. In 1992, Zane co-starred alongside Tilda Swinton in the film adaptation of Virginia Woolf's novel Orlando. In 1993, he played the Shakespearean actor "Mr. Fabian" in Tombstone and took a starring role in Sniper. Zane also starred alongside Mario Van Peebles as a cold-blooded and corrupt Colonel Graham in Posse and also in Lake Consequence and played a playboy named Harry, posing as the elusive, albeit fake Damon Bradley alongside Marisa Tomei and Robert Downey Jr. in Only You.

Zane also starred in a couple of Tales from the Crypt productions, including Tales From the Crypt Presents: Demon Knight, where he played a henchman of Satan called The Collector, and the episode "Well-Cooked Hams", where he played a poorly skilled magician who killed to steal good tricks from other magicians. In 1996, Zane played the eponymous classic comic book hero in the big budget action film The Phantom, based on Lee Falk's comic.

Zane played the snobbish millionaire misanthrope Caledon Hockley in James Cameron's 1997 blockbuster Titanic. This role as Rose's (played by Kate Winslet) fiancé earned him an MTV Movie Award nomination for "Best Villain" and a Blockbuster Entertainment Award. Along with the rest of the ensemble cast, he was nominated for a SAG award.

In 1998, Zane starred in and produced I Woke Up Early the Day I Died, a silent film based on Ed Wood's last script, intended as a parody on bad filmmaking. He won several awards at the B-Movie Film Festival, including Best Movie and Best Actor, for this work. The year after, he starred opposite Timothy Dalton, Bruce Payne, Sean Pertwee and Leonor Varela (who became his fiancé after shooting ended) in a miniseries about Cleopatra. Zane played the role of Mark Antony.

The same year, Zane voiced John Rolfe in Disney's Pocahontas II: Journey to a New World and Etrigan the Demon in an episode of The New Batman Adventures.

Zane appeared as neo-fascist Curtis Zampf in The Believer, which won the Grand Jury Prize at Sundance Film Festival in 2001. The same year, he also had a cameo as himself in the comedy Zoolander.

Zane appeared on Broadway in the musical Chicago, where he played lawyer Billy Flynn.

Zane also had a recurring role in the television series Charmed in which he played poetry-loving ex-demon Drake. He also provided the voice of Ansem, the main antagonist of the 2002 video game Kingdom Hearts, opposite Haley Joel Osment as Sora. Though archive audio of Zane was later used for Kingdom Hearts: Chain of Memories, he was replaced by Richard Epcar for the rest of the series from Kingdom Hearts II onwards. However, Zane's performance was kept for the Kingdom Hearts Final Mix remaster in Kingdom Hearts HD 1.5 Remix.

In 2006, Zane starred in Arthur Allan Seidelman's West End production of Six Dance Lessons in Six Weeks as an acerbic gay dance instructor opposite Claire Bloom.^[7] In the same year, he appeared in the Turkish film Valley of the Wolves: Iraq (Kurtlar Vadisi: Irak in Turkish), part of the Kurtlar Vadisi franchise. The film tells the story of the U.S. Army run amok in Iraq, eventually brought into check by a Turkish soldier. Zane plays Sam William Marshall, a cruel U.S. soldier who is the film's main antagonist.

He took over Timothy Olyphant's role as Christina Applegate's ex-boyfriend on Samantha Who?. However, the sitcom was not renewed for the 2009–2010 season.^[8]

Zane is a principal at RadioactiveGiant, a film and television production and distribution company.^[9]

Zane starred in the action/thriller film The Kill Hole (2012),^[10] and in January 2017 he appeared in a commercial for KFC as a gold-colored Colonel Sanders to pitch the restaurant chain's newest limited-time flavor, Georgia Gold Honey Mustard BBQ chicken.^[11] Zane also appeared in an episode of Community, season 6's "Advanced Safety Features".

Zane was also featured in two episodes of The Boys portraying a fictional version of himself who made a movie with Popclaw and also attended a comic convention with Tara Reid. In season 3, Zane appeared as himself portraying Alastair Adana in the Vought film Not Without My Dolphin.

In 2024, Zane portrayed Larry Ray in the Lifetime film Devil on Campus: The Larry Ray Story as part of its "Ripped from the Headlines" feature films.^[12]

Zane was married to actress Lisa Collins from 1989 to 1995. He was also engaged for a time to Chilean actress Leonor Varela who was his co-star in the miniseries Cleopatra (1999).^[13]

Later Zane was engaged to British model-turned-actress Kelly Brook; he met her when they co-starred in the movie Survival Island (2005), also known as Three. They split in April 2008, got back together again shortly after that, and ended the relationship in August 2008.^{[citation needed]} Zane dated Croatian model Jasmina Hdagha in 2010; they broke up later that year.^[14]

Through a friend, he met American model Candice Neil with whom he has two daughters; they became engaged.^[13][15] Their first daughter, Ava Catherine, was born in 2011, and their second daughter, Gia, was born in 2014.^[16]

In 1999, Zane participated in the first Gumball 3000 rally, driving a 1964 Aston Martin DB5.^[17] He is an abstract expressionist painter and he has had many solo and group exhibitions.^[18]

Zane executive-produced an album by bluesman Tim O'Connor that includes three songs from Dead Calm, in which Zane had one of the lead roles.^[19]