The Irish rockers, who are rumoured to be releasing a new album next year, saw off competition from acts including Take That and Katy Perry with their worldwide '360°' show.
U2's worldwide tour earned $293m (£186m) across 44 sold-out concerts. The shows attracted a total of 2,887,972 fans.
Bon Jovi, whose lead singer was falsely reported dead this week, claimed the second spot, earning $192m (£122m) from 68 shows attended by 1,851,385 fans.
Take That came in third with their 'Progress' tour, previously named as the highest-grossing in UK history.
Kenny Chesney, Usher, Lady Gaga, Andre Rieu and Sade also claimed top ten spaces, along with Michael Buble, Katy Perry, Lil Wayne, Justin Bieber, Glee, Britney Spears and Iron Maiden.
Billboard Boxscore's figures were based on ticket sales during the period between November 1, 2010 and November 8, 2011.
Watch U2 speak to NASA Commander Mark Kelly during their '360°' world tour below: