His submission to Weekly Shōnen Jump caught the attention of editor Taizo Nakamura and, at the age of 20, Inoue dropped out of college to move to Tokyo and pursue a career as a manga artist.

Inoue's first real fame came with his next manga, Slam Dunk, about a basketball team from Shohoku High School.

[8] It is about a basketball team from Earth that attempts to compete on the intergalactic level, it appears on his official website in four languages: Japanese, English, Chinese, and Korean.

Vagabond was Inoue's next manga, adapted from the fictionalized accounts by Eiji Yoshikawa of the samurai Miyamoto Musashi, which he began drawing in 1998.

Inoue also created character designs for the Xbox 360 RPG, Lost Odyssey, based on initial material provided by Hironobu Sakaguchi.

[13] In March 2011, Inoue painted large images of the Buddhist leader Shinran on twelve folding screens for display at the East Hongan Temple in Kyoto.

[15][16] In 2013, Takehiko Inoue was appointed by the Japanese Foreign Ministry to serve as an ambassador to celebrate Japan and Spain 400 years of goodwill until July 31, 2014.