The Scream stars separated in 2010 and on Friday (08Jun12), Arquette filed legal papers in a Los Angeles, citing irreconcilable differences.
He is asking for joint legal and physical custody of the couple's daughter, Coco, who turns eight on Wednesday (13Jun12).
According to the documents, obtained by TMZ.com, Arquette, who is now dating U.S. TV reporter Christina McLarty, will be representing himself in the divorce.
Ironically, the news of the divorce falls on the 13th anniversary of Arquette and Cox's wedding day (12Jun12).
The couple has remained close following its break-up and has continued to work together as TV and film production partners.