The band hit the Pyramid Stage in style, playing 'Even Better Than The Real Thing' with women's mouths projected onto the stage to keep them company.
A sign flashed up stating: 'Everything you know is wrong,' while other messages on the stage read: 'Believe,' with 'lie' highlighted in red.
"There's a very special feeling," said Bono. "Thanks for having us here." He then launched into the band's 1992 single 'One'.
Bono sung part of 'Jerusalem' before playing 'Where The Streets Have No Name' - to which the crowd cheered along in the damp conditions.
"It's not often you get an Irish man singing along to 'Jerusalem', so I hope you enjoyed it," Bono joked between songs.
Introducing the band, Bono described The Edge as a sorcerer before playing 'I Still Haven't Found What I'm Looking For'.
"The future needs a big kiss," was Bono's introduction to 2009 track 'Get On Your Boots'.
The band went on to treat the crowd to 'Sunday Bloody Sunday' and rattled through a few more classic tracks before thanking the festival-goers and the BBC viewers for watching.
There was still time for an encore, which included 'With Or Without You' and snippets of songs by Coldplay, Primal Scream and Beyoncé, who will all be performing over the rest of the Glastonbury weekend.
U2's setlist was as follows:
1. Even Better Than The Real Thing
2. The Fly
3. Mysterious Ways
4. Until The End Of The World
6. Where The Streets Have No Name
7. I Will Follow
8. I Still Haven't Found What I'm Looking For
9. Stay (Faraway, So Close!)
10. Beautiful Day
12. Get On Your Boots
14. Sunday Bloody Sunday
16. Pride (In The Name Of Love)
17. With Or Without You
18. Moment Of Surrender
19. Out Of Control
> Morrissey slams David Cameron in Glastonbury set
> Biffy Clyro channel Beyoncé at Glastonbury
> Glastonbury 2011: In pictures
Digital Spy is bringing you news from Glastonbury festival 2011 all weekend - view our guide to the festival and click here to stay abreast of our full coverage
Watch U2 discussing their Glastonbury set with the BBC below: