Jurors awarded Mr Depp - who denied abusing Ms Heard - $15m (£12m) in compensatory and punitive damages.
Ms Heard, 36, won one of three counter-claims against Mr Depp, 58, and was awarded $2m in compensatory damages.
The Hollywood actors, who divorced in 2017, presented warring versions during the trial of their doomed relationship.
Over six weeks, the court in Fairfax, Virginia, heard tawdry details of Mr Depp and Ms Heard's volatile marriage, and its unhappy ending.
Polls suggested more Americans were interested in the courtroom drama than the war in Ukraine or a potentially historic ruling on abortion expected any day from the US Supreme Court.
Coverage of the trial - which was televised and livestreamed - hit billions of views on social media.
After nearly two days of deliberations, jurors found on Wednesday that Ms Heard's statements about her marriage were "false" and she had acted with "actual malice".
But they also found that Mr Depp had defamed Ms Heard when his lawyer gave a statement to the Daily Mail in 2020 calling her abuse allegations a hoax.
As the seven-member jury delivered its verdict, screams and chants of "Johnny, Johnny, Johnny" erupted outside the court.
Mr Depp was not in court due to "previously scheduled work commitments", his spokesperson said. The actor was said to be watching from the United Kingdom, where he has played three surprise concerts alongside his friend, British musician Jeff Beck, since the jury began deliberating on Friday.
On the eve of the verdict, Mr Depp received a standing ovation after performing with Mr Beck at the Royal Albert Hall in London.
In a statement on Wednesday, he said "the jury gave me my life back. I am truly humbled."
He added, in Latin: "Truth never perishes."