The season is produced by Berlanti Productions, Warner Bros. Television and DC Entertainment, with Jessica Queller and Robert Rovner serving as showrunners.

Melissa Benoist stars as Kara, with principal cast members Chyler Leigh, Katie McGrath, Jesse Rath, Nicole Maines, Azie Tesfai, Julie Gonzalo, Staz Nair and David Harewood also returning from previous seasons.

[31] Melissa Benoist, who portrays Kara Danvers / Supergirl, said the season serves as a "self-exploration" for her character, "looking in the mirror and [contemplating] what her power means because it's almost limitless and it makes her so strong on Earth".

[32] Main cast members Melissa Benoist, Chyler Leigh, Katie McGrath, Jesse Rath, Nicole Maines, Azie Tesfai, Julie Gonzalo, Staz Nair and David Harewood will return as Kara Danvers / Supergirl, Alex Danvers, Lena Luthor, Querl Dox / Brainiac 5, Nia Nal / Dreamer,[33] Kelly Olsen,[30] Andrea Rojas,[34] William Dey,[35] and J'onn J'onzz / Martian Manhunter.

[36] In December 2020, David Ramsey was revealed to be reprising his Arrow role of John Diggle in addition to directing at least one episode in the season.

In the third episode, Peta Sergeant debuted as series regular as fifth-dimensional imp, Nyxly, who would serve as the season's main villain.