After an emotional debate during which several speakers shed tears, EU lawmakers voted 621 for and 49 against the Brexit agreement sealed between Britain and the 27 other member states last October, more than three years since Britons voted out.
Thirteen lawmakers abstained and the chamber then broke into a rendition of Auld Lang Syne, a traditional Scottish folk song of farewell.
Britain's 73 departing EU lawmakers headed for an "Au Revoir" party in the EU chamber after the vote.
Earlier on Wednesday, Britain's ambassador to the EU handed documents formalizing Brexit to a senior EU official.
Against a backdrop of British and EU flags at the bloc's Brussels headquarters, Tim Barrow, smiling, passed over a dark blue leather file embossed with the emblem of the United Kingdom.