MEPs ratified the Brexit Withdrawal Agreement by 621 votes to 49 following an emotional debate in Brussels.
After the vote, MEPs marked the UK's exit by singing Auld Lang Syne.
Several British MEPs said they hoped the UK would return one day although Eurosceptics, including the Brexit Party's Nigel Farage, used their final speeches to tear into the EU.
The UK is due to leave the bloc at 23:00 GMT on Friday.
Ratification of the withdrawal agreement, agreed by the UK and EU in October, was not in doubt after it easily cleared its committee stage last week.