Adele, 24, who last year became the first artist to secure three iTunes milestones with top-selling album, single and artist of the year, came in ahead of country-pop star Taylor Swift's "Red" and British folk band Mumford & Sons' "Babel."
ITunes did not reveal its sales or download figures.
British boy band One Direction's debut album "Up All Night" and current Grammy nominees fun.'s debut "Some Nights" rounded out the five top-selling albums on iTunes in the United States.
"21," released in February 2011, has performed strongly in the U.S. music charts this year following the singer's Grammy-sweeping win in six categories in February 2012.
Adele also landed Screen Actors Guild and Golden Globe nominations for her sultry James Bond theme song "Skyfall" this week, becoming a strong contender in the best song category for Hollywood's awards season.
"Thank you so much for the honour of being included in something as brilliant as the Golden Globes! Never in a million years did I ever think I'd come close to such a thing! Truly wonderful ... thank you to the Bond family for giving me the opportunity," the singer said in a statement on Thursday.
ITunes U.S. compiled their Best of 2012 list by looking at the most downloaded items from the Apple iTunes store.
Canadian pop star Carly Rae Jepsen had the top-selling track for her infectious breakthrough summer single "Call Me Maybe."
Post-apocalyptic action film "The Hunger Games" was the best-selling movie while the second season of British aristocratic period drama "Downton Abbey," another Hollywood awards favorite, was iTunes' top-selling television series.
The iTunes Best of 2012 lists can be seen at www.itunes.com/AppStoreBestof2012