The 23-year-old recording star also made a triumphant return to the stage after undergoing throat surgery and canceling a U.S. concert tour last year.
She looked radiant as she sang her hit "Rolling in the Deep," which won the awards for Song of the Year, Record of the Year and Short Form Music Video.
Adele also scooped up the prizes for Pop Solo Performance for her song "Someone Like You." In addition to winning the Album of the Year title, "21" also earned the statuette for Pop Vocal Album.
She went into Sunday's competition with six nominations and won all of her categories.
"Thank you so much," Adele tearfully said as she collected her final award of the night. "This record is inspired by something really normal and everyone's been through it, which is a rubbish relationship. And it's gone on to do things, I can't tell you how I feel about it. It's been the most life-changing year."
Foo Fighters won the Grammys for Long Form Music Video for "Foo Fighters: Back and Forth," Hard Rock/Metal Performance for "White Limo,"
Rock Song and Rock Performance for "Walk" and Rock Album for "Wasting Light."
The prize for Rap Performance went to Jay-Z and Kanye West for "Otis." The Rap/Sung Collaboration trophy was shared by West, Rihanna, Kid Cudi and Fergie for "All of the Lights," which also won the title for Best Rap Song. West also picked up the award for Rap Album for "My Beautiful Dark Twisted Fantasy."
The Grammy for Traditional Pop Vocal Album was awarded to "Duets II" by Tony Bennett and Various Artists. "Body and Soul," a track Bennett recorded with Amy Winehouse before she died last year, won the prize for Pop Duo/Group Performance.
Cee Lo Green picked up the awards for Traditional R&B Performance and R&B Song for "Fool for You."
Taylor Swift went home with the trophies for Country Solo Performance and Country Song for "Mean."
The evening featured tributes to late music industry titans Etta James, Don Cornelius and Whitney Houston, and performances by the Beach Boys, Katy Perry, Paul McCartney, Maroon 5, Foster the People, Rihanna, Coldplay, Bruce Springsteen and the E Street Band, Taylor Swift, Bruno Mars, Chris Brown, Alicia Keys and Bonnie Raitt.
LL Cool J served as host of the event.