The season is produced by Berlanti Productions, Warner Bros. Television, and DC Entertainment, with Eric Wallace serving as showrunner.

Grant Gustin stars as Barry, with principal cast members Candice Patton, Danielle Panabaker, Carlos Valdes, Hartley Sawyer, Danielle Nicolet, Tom Cavanagh, and Jesse L. Martin also returning from previous seasons, while LaMonica Garrett was promoted to series regular from his guest status in season five.

They are joined by new cast member Efrat Dor while former series regular Keiynan Lonsdale makes a guest appearance.

While the heroes regroup, the Anti-Monitor sends a brainwashed Harbinger to attack them and kill the Monitor so he can finish destroying the multiverse.

Before he and the rest of the team is killed, Pariah teleports the Paragons to the Vanishing Point, where they learn Lex Luthor used the Book of Destiny to replace Earth-96's Superman with himself.

[51] Wallace felt episode 19, which became the season finale due to the COVID-19 pandemic halting all production, worked in the series' favor because it had "a big cliffhanger" that was "a good pause point".

Wallace conceded there may be a few small adjustments made based on how the pandemic would affect shooting, but said Eva McCulloch's story "is on a very specific trajectory that we want to honor and finish."

[51] Main cast members Grant Gustin, Candice Patton, Danielle Panabaker, Carlos Valdes, Hartley Sawyer, Danielle Nicolet and Jesse L. Martin return as Barry Allen / Flash, Iris West-Allen, Caitlin Snow / Frost, Cisco Ramon, Ralph Dibny / Elongated Man, Cecile Horton, and Joe West.

[55] Sendhil Ramamurthy was cast in a recurring role as Ramsey Rosso / Bloodwork, the Big Bad of the season's first half.