After the 2015 finale of CSI: Crime Scene Investigation, series creator Anthony E. Zuiker described what he imagined the characters' futures would be, including Grissom and Sara sailing the oceans and having children, and Catherine still running the crime lab.

Following the 2016 cancellation of CSI: Cyber, the last CSI series at the time, producers and CBS Entertainment president Glenn Geller expressed openness to reviving the franchise in another incarnation.

The series was originally conceived as an event/limited series sequel before being greenlit to a full straight-to-series order in March 2021, with the possibility left open that it could become an ongoing show.

William Petersen and Jorja Fox were in talks as early as February 2020 to reprise their original roles of Gil Grissom and Sara Sidle, finally being officially cast alongside Wallace Langham's return as David Hodges in March 2021.

Matt Lauria and Mel Rodriguez had both previously guest-starred as different characters elsewhere in the CSI franchise before being cast as new series regulars in CSI: Vegas.

Petersen, Fox, and Rodriguez all departed the show ahead of season two, with Marg Helgenberger joining instead to reprise her original role as Catherine Willows.

Filming was originally meant to begin in fall 2020 but was delayed due to COVID-19 production shutdowns, eventually starting on May 4, 2021, in Los Angeles, California.

On August 22, 2021, William Petersen was hospitalized after becoming ill during filming of the series.

The show's premiere date of October 6, 2021, was chosen to mark 21 years since the original premiere of CSI: Crime Scene Investigation, after an earlier plan to launch on the exact 20th anniversary in 2020 was scrapped due to pandemic delays.