In a joint statement issued Wednesday by the mayor's office, the Newsoms cited the strain posed by their high-profile, bicoastal careers as the reason for the split.
"It is with great sadness that we announce today that we have decided to end our marriage. Unfortunately, the demands of our respective careers have made it too difficult for us to continue as a married couple," they wrote. "We will remain close friends."
The couple, who were featured in September's Harper's Bazaar magazine as "The New Kennedys," went public with their news after sharing it with their families and friends on Wednesday, according to Peter Ragone, the mayor's spokesman. Ragone said neither was available for additional comment.
Newsom, a Democrat, made headlines last year by granting marriage licenses to same-sex couples.
Just after he took office, his wife, a former model and San Francisco assistant district attorney, moved to New York City to pursue her television career.