Limited by his parents to buying one manga book a month, Otomo typically chose Kobunsha's Shōnen magazine, which included Astro Boy by Osamu Tezuka and Tetsujin 28-go by Mitsuteru Yokoyama, series which he would copy drawing in elementary school.

At this time, one of his friends introduced him to an editor at Futabasha, who, after seeing Otomo's manga, told the high school student to contact him if he moved to Tokyo after graduating.

[7] On October 4, 1973, Otomo published his first work, a manga adaptation of Prosper Mérimée's short story Mateo Falcone, titled A Gun Report.

[8] In 1979, after writing multiple short-stories for the magazine Weekly Manga Action, Otomo created his first science-fiction work, titled Fireball.

[10] In a collaboration with writer Toshihiko Yahagi, Otomo illustrated Kibun wa mō Sensō about a fictional war that erupts in the border between China and the Soviet Union.

[10] 38 years later, the two created the one-shot sequel Kibun wa mō Sensō 3 (Datta Kamo Shirenai) for the April 16, 2019 issue of the magazine.

[13] Otomo created the one-shot Hi no Yōjin about people who put out fires in Japan's Edo period for the debut issue of Comic Cue in January 1995.

Intended to capture the region's will to overcome the natural disaster, it has been located on the first floor of the terminal building at Sendai Airport since March 2015.

[18] Planning to draw the work that is set during Japan's Meiji period without assistants, he was initially targeting a younger audience, but said the story had developed more towards an older one.

It was noted that some of his manga were edited when initially compiled into book format, and this new project, personally overseen by Otomo, restored them to how they appeared in their original serialization.

[26] In 2013, Otomo took part in Short Peace, an anthology consisting on 4 short films; he directed Combustible, a tragic love story set in the Edo period based on his 1995 manga Hi no Yōjin,[14] while Hajime Katoki directed A Farewell to Weapons, depicting a battle in a ruined Tokyo based on Otomo's 1981 manga of the same name.

[29] In 2019, he announced that he is writing and directing an animated film adaptation of his 2001 manga Orbital Era with Sunrise and released a trailer that same year.

He believes this habit of drawing detailed backgrounds was influenced by Shigeru Mizuki's manga, which showed him how important backdrops are to a story.

[31] Otomo strongly praised the framing done by Tetsuya Chiba, whose work he studied a lot out of admiration at a store in Kichijoji, for making it easy to grasp how tangible the backgrounds and characters are.

He also stated that he is a fan of mecha by Takashi Watabe and Makoto Kobayashi and is fond of those seen in Neon Genesis Evangelion, but explained that all his influences are jumbled and mixed together; "In short, I digest many different things and ideas tend to pop out from that.

[35][36][37] When talking in 1997 about the future of manga, Urasawa opined that [Osamu] Tezuka created the form that exists today, then caricatures appeared next, and comics changed again when Katsuhiro Otomo came on the scene.

[39] The Dragon Ball manga creator Akira Toriyama was interviewed on who was his favorite manga artist, and said that he found his peer Otomo to be “incredible.”[40] Otomo's manga work also notably influenced a number of Japanese video game designers by the mid-1980s, including Enix's Yuji Horii (The Portopia Serial Murder Case and Dragon Quest), Capcom's Noritaka Funamizu (Gun.Smoke and Hyper Dyne Side Arms), UPL's Tsutomu Fujisawa (Ninja-Kid), Thinking Rabbit's Hiroyuki Imabayashi (Sokoban), dB-SOFT's Naoto Shinada (Volguard), Hot-B's Jun Kuriyama (Psychic City), and Microcabin's Masashi Katou (Eiyuu Densetsu Saga).

[43] In 2017, the book Otomo: A Global Tribute to the Mind Behind Akira was published in Japan, France and the United States, featuring writing and artwork from 80 artists such as Masakazu Katsura, Taiyo Matsumoto, Masamune Shirow, Asaf and Tomer Hanuka, and Stan Sakai.

He also oversaw the composition of the Spriggan animated film[50] and directed the music video Juku-Hatachi (じゅうくはたち) for Aya Nakano.