In June 2006, Shueisha announced that the D.Gray-man manga would be adapted into an anime, which began airing on TV Tokyo on October 3, 2006.

During production, manga author Katsura Hoshino often visited the TMS Entertainment studio, where voice actors asked her for advice about their characters; she was nervous but impressed by their dedication, especially Sanae Kobayashi (Allen), Takahiro Sakurai (Kanda), Katsuyuki Konishi (Komui), and Hiroki Tōchi (Cross Marian).

Hoshino jokingly said that the character Lenalee seemed more beautiful after seeing voice actress Shizuka Itō's performance.

When Hoshino was shown an early version of the first opening theme, 'Innocent Sorrow' by the band Abingdon Boys School, she began to cry in delight while the production staff laughed.

Tyki Mikk's voice actor, Toshiyuki Morikawa, described the recording sessions as 'lively' due to the presence of many popular actors, and the cast remained friends and kept in touch after the anime finished.

The anime included original content not featured in the manga to give Hoshino material to adapt, but these episodes often contradicted her original story, leading to criticism that eventually contributed to the series' cancellation.

English voice actor Todd Haberkorn said that despite generally positive reviews, DVD sales for the series were poor, and he encouraged fans to buy DVDs on sale to prevent the series from being cancelled.

Voice actor Travis Willingham was considered miscast as Kanda in the English dub by Animation Insider, while Neo praised Junpei Takiguchi's Japanese performance as the Millennium Earl as far superior to Jason Liebrecht's English dub version.