Heard, 30, and Depp, 52, have been married since February 2015.
She filed for divorce in Los Angeles Superior Court on Sunday citing irreconcilable differences and requested spousal support, according to court records. They have no children.
Depp and Heard made headlines last year after being charged with illegally bringing their two dogs into Australia, which has strict biosecurity laws regarding foreign animals.
Heard pleaded guilty to knowingly producing a false or misleading document, while two other charges of illegally importing her dogs were dismissed. She was spared a conviction over the incident and given a one-month good behavior bond sentence instead.
Depp, who was filming the latest installment of "Pirates of the Caribbean" franchise during the incident, and Heard then released a strange but somber apology video, which Depp has since had a bit of fun with.
He's also started taking shots at the man who threatened to euthanize their two terriers, former agriculture minister and current Deputy Prime Minister Barnaby Joyce, saying the politician looked like he was "inbred with a tomato" on "Jimmy Kimmel Live" Wednesday.
It's not clear who will get to keep the dogs.
Depp's newest film, "Alice Through the Looking Glass," opens in theaters Friday.