Other major roles in anime include Leila Malcal in Code Geass: Akito the Exiled, Jeanne d'Arc in Fate/Apocrypha, Shiki Ryōgi in The Garden of Sinners, Eto in Tokyo Ghoul, Riho Yamazaki in Nightwalker: The Midnight Detective, Moe Katsuragi in Risky Safety, Princess Tomoyo in Tsubasa: Reservoir Chronicle, Haruhi Fujioka in Ouran High School Host Club, Sayaka Nakasugi in Birdy the Mighty, Ciel Phantomhive in Black Butler, Shinobu Oshino in Monogatari, Lunamaria Hawke in Mobile Suit Gundam SEED Destiny, Merlin in The Seven Deadly Sins, Motoko Kusanagi in Ghost in the Shell: Arise, Quinella in season 3 of Sword Art Online, and Echidna in Re:Zero − Starting Life in Another World.

[8] In video games, Sakamoto voices Aigis in Persona 3, Maki Harukawa in Danganronpa V3: Killing Harmony, Aerith Gainsborough in Compilation of Final Fantasy VII, Aura and Natsume in .hack, La Mariposa in Dead or Alive, Lightning in the Final Fantasy XIII games, Ling Xiaoyu in Tekken, and Alisa Ilinichina Amiella in God Eater.

In 2002, Sakamoto worked again with Kanno and Yūho Iwasato for her 10th single, "Hemisphere", the opening theme for the TV anime series RahXephon.

[19] This year she also starred in her first TV drama Suekko Chounan Ane San-nin, and also played the leading role in the short film 03† directed by Hidenori Sugimori.

[22] On the other hand, Sakamoto's 11th single "Tune the Rainbow" (Released on April 2, 2003), which was used as the main theme song for RahXephon: Pluralitas Concentio, The only anime movie that was nominated for the 35th Seiun Award for Best Dramatic Presentation.

[24] Her fifth album, Yūnagi Loop, released on October 26, 2005, was her first co-produced by herself along with musician Mistuyoshi Tamura, whom she would continue working in her subsequent records.

For this album's, Sakamoto has collaborated with many various well-known lyricist and composers, including Yūho Iwasato, Haruichi Shindō, Robin Fredriksson[f] and Shusui.

In 2010, Sakamoto celebrated her 15th anniversary in the entertainment industry, releasing on March 31—her 30th birthday—her greatest hits album Everywhere, and also holding a concert at the Nippon Budokan.

The album, titled Singer Song Writer, featured two new versions of Sakamoto's previous compositions "Everywhere" and "Chikai", as well as eight original tracks.

[i][28] Sakamoto first worked with the composer Yoko Kanno in her 1996 debut single, "Yakusoku wa Iranai" ("Promises Not Needed"), which was used as the opening theme for the anime series The Vision of Escaflowne.

[284] In addition, in the first Seiyu Awards, she was nominated for "Best Actress in a leading role" for her portrayal of Haruhi Fujioka in Ouran High School Host Club as well as "Best Musical Performance" for Tsubasa Chronicle's ending theme Loop.