In the song, Spears and Madonna sing of the pleasures of letting go on the dancefloor, in lyrics such as "I'm up against the speaker / Trying to take on the music / It's like a competition".
Po podatkih spletne strani Musicnotes.com, ki je v lasti podjetja Hal Leonard Corporation, se vokali Britney Spears in Madonne v pesmi »Me Against the Music« raztezajo od F3 do B4.