Bono gave props to Springsteen for standing in for him on vocals for the World Aids Day RED benefit in Times Square when, he said, "I busted myself up here in the city."
"This man showed up... delivered," he said, as the Garden erupted in cheers of "Bruuuce."
Bono also acknowledged Clinton and all the peacemakers aiding Ireland during "Pride (In the Name of Love)."
The evening was special for fans of the Irish band, who were treated to a performance of "Trash, Trampoline and the Party Girl," which was prominently featured on the group's live album, Under a Blood Red Sky. The quartet sprinkled a little magic at the end with the closer "40," as each member made its way off the stage.
Springsteen's appearance capped off U2's North American tour and a stretch of shows that included guest turns from Jimmy Fallon, The Roots, Lady Gaga and Paul Simon.
Many celebrities turned out for the shows, including Paul McCartney, Nile Rodgers, Alicia Keys , Jon Bon Jovi, Coldplay's Chris Martin, comedian Chris Rock, producer Steve Lillywhite, model Christy Turlington, MTV personality Matt Pinfield and filmmaker Steven Soderbergh.