The London folk-rock band scooped album of the year –arguably the top award of the night – with their second album Babel.
Lead singer Marcus Mumford, who picked up the award from Adele, said: "We figured we weren't going to win anything because The Black Keys have been sweeping up all day, rightfully so."
Adele continued her run of success picking up the award for pop solo performance of the song Set Fire To The Rain (Live), which features on her best-selling album 21.
The pop singer picked up six awards at last year's Grammys following the release of her hugely successful second album.
At the ceremony in Los Angeles veteran singer-songwriter Sir Elton John teamed up with the new generation in his field Ed Sheeran, to perform the hit A-Team.
Another top winner on the night was Beyonce, who took the award for best traditional R&B performance.