Born to a family of entertainers, Big is the youngest brother of actors Rosanna Arquette, Patricia Arquette, and Alexis Arquette, and the son of veteran bit-part actor Lewis Arquette. During David's early years the family lived on a California commune, but moved to Los Angeles so that Rosanna could pursue an acting career.

At the encouragement of his family, Arquette also pursued acting and acquired roles on the TV series The Outsiders and Parenthood. David first brought his quirky, eccentric persona to the small screen in 1989 with a television adaptation of The Outsiders. He had his big screen debut in 1992 when he performed in a number of films including Buffy the Vampire Slayer and Where the Day Takes You. Small roles in subsequent features followed, including 1994's Airheads, but it wasn't until his turn as a bumbling deputy in Wes Craven's Scream (1996) that he began to receive wider recognition. The same year, his visibility was further increased by a secondary role in Beautiful Girls and his turn as a struggling prostitute in Johns.

A year later, Scream's highly successful sequel, the aptly titled Scream 2, was released. In addition, it brought Dream with the Fishes, a film that Arquette both acted in and co-produced. His mother's death from cancer that year also prompted a drug-use spiral. Luckily for him, his girlfriend Courteney Cox whom he met on the set of Scream, helped him get through it.

The year 1999 was a busy for the actor, signaling that Hollywood was finding more room to accommodate his offbeat talent. In addition to his recurring spot in a series of creepy AT&T commercials, Arquette had major roles in three movies, the Drew Barrymoreromantic comedy Never Been Kissed, Muppets From Space, and Antonia Bird's much maligned Ravenous. Arquette further increased his Hollywood visibility with his marriage to Cox in April 1999. They then went on to appear in the final installment of the slasher series, Scream 3, which came out in February 2000. Arquette played the starring role in See Spot Run (2001), a family comedy in which a mailman has to take care of a dog who is, unbeknownst to him, an FBI drug-sniffing superdog that escaped from a witness protection program. He made $5 million starring in Eight Legged Freaks (2002), but unfortunately, the film didn't take off at the box office. Arquette continues to work steadily, but is still looking for the one big role in a major movie that will propel him to the Hollywood A-list. In the meantime, he has also been visible in a widely-seen soft drink commercial alongside Courtney Cox in which they play themselves, and does commercials as the "1-800-CALL-ATT Guy."