Mortimer, best known for his comedy shows with Vic Reeves, will feature in a TVC for the beer brand as the Bombardier character leading his troops into battle "somewhere hot and a tad dangerous".
It will launch on St George's Day, 23 April, and will be supported by a social media push.
Phil Toms, the director of Charles Wells brands, said: "Bob Mortimer enters the fray as Bombardier Bedford following the sad loss of his predecessor and makes an instant impression.
"I’m thrilled that we have one of the country’s most original comedy talents... We believe he’ll have a great connection with licensees and drinkers as he leads the charge for a quality pint of Bombardier."
Mortimer will hero the brand's Bombardier Burning Gold variant, said marketing manager Emily Hudson.
She said: "Our mission is to connect with drinkers through the Bombardier regiment of beers, of which there are now two variants.
"The hero of this campaign is Bombardier Burning Gold, the next in line in the Bombardier chain of command, and picks up from where our original Bombardier Bedford was lost in battle."
Rik Mayall had portrayed the brand's character since 2011, until he passed away in 2014. Following his death, the Wells and Young’s-owned brand temporarily ceased Twitter activity and wound down its consumer-facing marketing as a mark of respect before firing up again in August.
Bombardier assured that the transition to Bob Mortimer playing the role would be a "sympathetic one".