In April 1995, Arquette married Nicolas Cage (whom she would later co-star with in Bringing Out the Dead in 1999). They separated after nine months, but acted as a couple in public until Cage filed for divorce in February 2000. The divorce petition was withdrawn, but Arquette filed again in November 2000.

She and actor Thomas Jane became engaged in 2002 and married on June 25, 2006 at the Palazzo Contarini in Venice, Italy. They have a daughter, Harlow Olivia Calliope, whom Arquette discovered she was carrying while filming Holes, born on February 20, 2003. Arquette also has a son, Enzo (b. 1989), from her previous relationship with musician Paul Rossi.

In 1997, after her mother died of breast cancer, Arquette worked to raise awareness about the disease. She has run in the annual Race for the Cure, and in 1999 was the spokesperson for Lee National Denim Day, which raises millions of dollars for breast cancer research and education.