Heard, 36, wrote on Instagram that she had made the "difficult" choice to settle, adding the decision was "not an act of concession".
She and Depp, 59, faced off in court earlier this year, where jurors heard intimate details of their relationship.
A jury then found Heard had defamed Depp in an article in which she said she was a victim of abuse.
The terms of the settlement were not immediately clear.
The BBC has reached out to Depp's legal team for comment.