The rapper, real name Marshall Mathers Iii, topped the bill on the second night of the event, following punk trio Green Day after they performed on Friday night (23Aug13).
The crowd roared as Eminem, who was 20 minutes late, took the stage and opened with new single Survival, before playing hits including Lose Yourself and The Way I Am.
He told fans, "I feel like I'm not even working right now, just having fun. I think this is the loudest crowd we've ever had - I'm not joking."
Dido arrived unannounced when Eminem began his hit Stan, which features a sample of the singer's track Thank You. He hugged the Brit after they finished the song and told the audience, "Make some noise for Dido, y'all!"
Eminem was backed by a live band, and wrapped up the show with a medley of three of his greatest hits, My Name Is, The Real Slim Shady and Without Me.
The Grammy winner will repeat the set at Reading's sister site in Leeds on Sunday night (25Aug13).