According to TMZ, the couple separated "several months" ago, but continue to maintain a professional relationship and friendship.
In a statement, they said: "The reason for this separation is to better understand ourselves and the qualities we need in a partner and for our marriage. We remain best friends and responsible parents to our daughter and we still love each other deeply.
"As we go though this process we are determined to use kindness and understanding to get through this together."
They added: "We are comfortable with the boundaries that we have established for each other during this separation and we hope that our friends, family, fans and the media also show us respect, dignity, understanding and love at this time as well."
The pair met while filming Wes Craven horror film Scream in 1995 and married four years later.
Their daughter Coco Riley was born in 2004.
Cox and Arquette are currently reprising their roles for the fourth film in the Scream franchise, which is expected to be released next year.