Mack Sennett, a silent film producer and director, came to the San Fernando Valley and opened his new movie studio at this location (at what is now Ventura Boulevard and Radford Avenue) in May 1928.

He previously operated a smaller studio on Glendale Boulevard in Echo Park (then called Edendale) where he produced films featuring the Keystone Cops, Charlie Chaplin, Mabel Normand, Buster Keaton, W. C. Fields, and Fatty Arbuckle.

The new studio specialized in B-movies, including many Westerns starring the likes of Roy Rogers, Gene Autry, and John Wayne, all of whom gained their first breaks with Republic.

Also, Four Star Productions leased the lot for many of its series like The Rifleman, Dick Powell's Zane Grey Theater, and The Big Valley.

Almost immediately after leasing the Republic Pictures lot, CBS began to locate its network-produced filmed shows there, including Gunsmoke, My Three Sons, and Gilligan's Island.

[2] Since 2007, the Studio Center serves as the home to CBS's Los Angeles flagship TV station KCBS-TV, along with sister station KCAL-TV, as they vacated Columbia Square to move into a newly built, digitally-enhanced office and studio facility located where the house for the CBS reality series Big Brother once stood.

[3] In 2008, Entertainment Tonight and The Insider moved from the Paramount backlot to Studio Center, as CBS took ownership of the series after its spin-off from Viacom.

A re-merged ViacomCBS (now Paramount Global) announced in 2021 that it intended to sell the facility as part of a corporate effort to focus on content.

In February 2023, The Los Angeles Times reported that "Radford Studio Center is set to get a $1-billion upgrade to expand its facilities and bring them further into the digital age".

[7] Deadline Hollywood reported that the upgrades will include "modern soundstages, production and support offices, sustainability measures, historic preservation, and a transportation infrastructure.