Smith was given the nickname “Prince Charming” in high school, which he adapted to “Fresh Prince” in order to reflect a more hip-hop sound when he began his musical career. He formed an alliance with schoolmate and deejay Jeffrey Townes, whom he met in 1981. They began recording as DJ Jazzy Jeff and the Fresh Prince and released their first single, "Girls Ain't Nothing but Trouble," in 1986, later followed by the album Rock the House. In 1988 the group released the groundbreaking single "Parents Just Don't Understand," which went on to win a Grammy Award (the first Grammy ever presented in the rap performance category).

Smith's act, notable for its wide crossover appeal, was sometimes characterized as “light rap” because of the lack of hard-core lyrics and themes in his compositions. Platinum-certified recordings and accompanying videos subsequently brought him to the attention of television producers. The television sitcom The Fresh Prince of Bel-Air, which began in 1990 and was loosely based on Smith's real-life persona, ran on NBC for six successful seasons, ending at the star's request. During the series' run, Smith garnered two Golden Globe nominations and produced several episodes.

Buoyed by his small-screen success, Smith expanded into cinema with Where the Day Takes You (1992). His first dramatic role was in the film version of the successful stage play Six Degrees of Separation (1993). The action comedy-thriller Bad Boys (1995), however, proved to be the turning point in his film career. While the movie was not a critical success, it made more than $100 million worldwide, proving Smith's star power. In 1996 he starred in that year's number one movie, Independence Day. He again broke box-office records the next year with the science-fiction comedy Men in Black, for which he also recorded the Grammy-winning title song; the sequel to the film appeared in 2002. In 1998 Smith released his first solo album, Big Willie Style, which included the hit "Gettin' Jiggy Wit It," and starred in the dramatic thriller Enemy of the State.

After releasing the album Willenium in 1999, Smith demonstrated his remarkable versatility as an actor, playing an enigmatic golf caddy in The Legend of Bagger Vance (2000); the boxer Muhammad Ali (Ali, Muhammad) in the biopic Ali (2001); and a date doctor helping a romantically inept man find love in Hitch (2005). Lost and Found, Smith's fourth solo album, was released in March 2005. The next year he starred in and coproduced The Pursuit of Happyness, and his performance as a single father who overcomes adversity earned him an Academy Award nomination for best actor. In I Am Legend (2007), Smith appeared as a scientist who is perhaps the last human on Earth following an epidemic. Hancock (2008) featured Smith as a superhero trying to revamp his unpopular image, and in Seven Pounds (2008) he played a man seeking redemption after accidentally killing seven people in a car accident.