The season sees the return of the main cast members Rina Satō, Satomi Arai, Aki Toyosaki, and Kanae Itō, with the addition of Nozomi Sasaki and Atsushi Abe from A Certain Magical Index television series.

[21] In October 2012, Rina Satō, Satomi Arai, Aki Toyosaki, and Kanae Itō were confirmed to be reprising their respective roles from the first season as Mikoto Misaka, Kuroko Shirai, Kazari Uiharu, and Ruiko Saten,[15] with the addition of Nozomi Sasaki as the Sisters and Atsushi Abe as Toma Kamijo, both reprising their roles from A Certain Magical Index television series.

[12] Funimation announced in April 2014 the English dub cast for the series, including Mariela Ortiz as Nunotaba, Leah Clark as Seivelun, Lydia Mackay as Mugino, Apphia Yu as Kinuhata, and Megan Shipman as Takitsubo.

[29] In the same month, Satō, Arai, Toyosaki, and Itō were present at Anime Contents Expo 2013 in Makuhari Messe to promote the series,[30] where a 90-second promo video was released.

[54] Rebecca Silverman of Anime News Network graded A Certain Scientific Railgun S 'B', feeling that the Sisters story arc in the series was not rehashed as compared to its earlier portrayal from the first season of A Certain Magical Index and lauding Misaka's appearance in it.

[56] Tsukasa Kano, a science writer who graduated from Nihon University and member of the Space Authors Club, discussed human cloning in A Certain Scientific Railgun S. He stated that there is a possibility but currently impractical due to the low yield rate among humans, while contradicted the 14-day development of a clone to a full appearance of a junior high school student as depicted in the series since it naturally needs to grow for up to 14 years, which requires 80,000 eggs harvested from people and 80,000 women to serve as "borrowed bellies" for impregnation.

[58] An 80-page official visual book for the series was released on March 27, 2014, which was bundled with a Blu-ray disc containing a brand-new episode titled "All the Important Things I Learned in a Bathhouse" (大事なことはぜんぶ銭湯に教わった, Daiji na Koto wa Zenbu Sentō ni Osowatta).