Released as the album's lead single, the song became Jones' biggest hit, reaching the top ten in Ireland and on the US Billboard Hot 100. The song was most successful in the United Kingdom, where it peaked at number two on the UK Singles Chart. In addition, "U Know What's Up" topped Billboard's Hot R&B/Hip-Hop Songs for eight consecutive weeks, his only single to do so to date. A remix version featuring Left Eye of TLC was used in the accompanying music video.
The video begins with Left Eye at her apartment receiving a phone call, presumably from Jones, informing her that the music video for the song is being aired on TV. She turns to the TV screen behind her playing the video, which shows Jones at a hotel party, and proceeds to watch it. As it turns out, Left Eye is not the only person watching the video, as the video pans across the building showing Usher and his girlfriend at his apartment, and Big Boi hosting a music video premiere at his apartment. Midway through the video, Left Eye leaves her apartment and recites her verse in the song while walking across the corridor, presumably to join Jones at a similar party at the back of the building, which is revealed as the camera pulls back from the corridor. At the end, the video pulls back to reveal Jones watching it at his apartment with his girlfriend.