His career began upon being discovered by rapper Snoop Dogg in the late 1990s, eventually being brought to record producer Jermaine Dupri and signed to So So Def Recordings. As Lil' Bow Wow, he released his first album at age 13, Beware of Dog, in 2000, which was followed by Doggy Bag a year later.

In 2003, Bow Wow released his third album Unleashed, which was the first album released after dropping the "Lil'" from his stage name, and the first not to be released by So So Def. His next album, Wanted (2005), spawned his two highest-charting singles, "Let Me Hold You" (featuring Omarion) and "Like You" (featuring Ciara). In September 2015, Bow Wow signed a management deal with Puff Daddy's Bad Boy Records.

Bow Wow made his first movie appearance in the 2002 movie All About the Benjamins as a cameo. In the same year, Bow Wow made his debut as the lead role in Like Mike. He later began to undertake lead roles in movies, such as Johnson Family Vacation in 2004 and Roll Bounce in 2005. He also played a supporting role in the film The Fast and the Furious: Tokyo Drift in 2006, a character he reprised in F9 (2021). Bow Wow also appeared in five episodes of the television series Entourage, and starred as Brody Nelson in CSI: Cyber until the show's cancellation in 2016.