Author Nobuhiro Watsuki stated before the anime's premiere that he already considered his manga to have an 'anime-like' feel, but he feared the tight production schedule and had little direct involvement in the adaptation because of his busy schedule with weekly serialization.

Watsuki regretted that the voice actors from the CD dramas, especially Megumi Ogata (Kenshin) and Tomokazu Seki (Sanosuke), were not chosen for the anime; he himself personally apologized to Seki, but could not find Ogata and apologized through a recorded casual conversation.

Fans of Megumi Ogata sent letters requesting that she voice Seta Sōjirō in the anime, but Watsuki himself thought she would be more suited for the role of Misao, and he himself wished to voice the character Makimachi Misao... in fact Watsuki was hoping to participate as the voice of Misao (Makimachi Operetta).

Voice actress Mayo Suzukaze (Kenshin in the 1996 series) had already left the Takarazuka theater company before being cast, and was chosen for having a voice capable of appealing to adult women, an essential audience for the prime time ratings.

Singer Takanori Nishikawa, vocalist of T.M.Revolution who sang one of the opening themes, appeared as a guest character ('Ren of the Giant Serpent') in two episodes of the Black Knights arc.

The internet meme 'Futae no Kiwami, Aaah!', based on mistranslations ('kuchi-komi') from foreign language dubs of the series, went viral on the Japanese website Niconico Douga and generated many MAD videos; in a 2016 interview Watsuki himself confirmed he was aware of the phenomenon.

The ending theme 'the Fourth Avenue Café' by the band L'Arc-en-Ciel was taken off the air just four weeks after its debut and replaced again by 'Heart of Sword', due to the arrest of drummer sakura for violating the stimulant control law during the series' broadcast.

The animation production switched studios midway through the series: episodes 1 to 66 were produced by Studio Gallop, while from episode 67 onwards the production moved to Studio Deen, which also handled the subsequent OVAs.

Episode 95, which was never aired on television, was only released on video (VHS) in December 1998, months after the end of regular broadcast.

For the North American dub by Media Blasters, screenwriter Clark Cheng had difficulty translating Kenshin's characteristic speech patterns, such as the use of 'de gozaru' and the interjection 'oro', opting to replace them with expressions like 'that I did' and the sound 'huah' to preserve the original effect.