During production, 12 positive cases of COVID-19 were confirmed at the filming studio, but filming was not halted. The season was filmed at Red Studios Hollywood from the end of June 2021 to August 11, 2021. The buzzer provides the possibility of an immediate elimination, if the panelist who hits the buzzer is able to correctly identify the celebrity at that moment.

A new twist, titled the ' Take It Off Buzzer', debuted in the season. On August 30, 2021, it was announced that Leslie Jordan, Joel McHale, will.i.am, and Cheryl Hines would serve as guest panelists throughout the season. On August 12, 2021, a sneak peek special for Alter Ego and the new season of The Masked Singer was announced, which aired on September 12. On July 26, 2021, it was announced that the season would have a two-night premiere on September 22 and 23, 2021, followed by the series premiere of new series Alter Ego on both nights. Along with the teaser, it was revealed that host Cannon and panelists McCarthy, Jeong, Thicke, and Scherzinger would all be returning for the new season. On July 13, 2021, the first teaser for the season was released, giving some of the first clues. On May 17, 2021, FOX announced that the series was renewed for a sixth season with a targeted premiere during the 2021-22 television season.

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