Double world champion Fernando Alonso will skip this year's race around the principality's streets on May 28 to compete in the Indianapolis 500, which takes place on the same day.
McLaren won the Indy 500 three times during the 1970s but haven't entered a car for 38 years. This year, the UK-based team will field a Honda-powered car in collaboration with the Andretti Autosport team.
Alonso has been a permanent fixture on the grid at Monaco since 2003 and has won the race twice, in 2006 and 2007, but hasn't been on the podium since 2012, when he finished 3rd for Ferrari.
The temporary switch will be Alonso's first appearance in IndyCar but not his first at the Indianapolis Motor Speedway which hosted Formula One races from 2000 to 2007 -- albeit on a different track configuration.
"I've never raced an IndyCar car before, and neither have I ever driven on a super-speedway, but I'm confident that I'll get to grips with it fast," Alonso said in a statement on the McLaren website.
"I'm immensely excited that I'll be racing in this year's Indy 500, with McLaren, Honda and Andretti Autosport.
"The Indy 500 is one of the most famous races on the global motorsport calendar, rivaled only by the Le Mans 24 Hours and the Monaco Grand Prix, and it's of course a regret of mine that I won't be able to race at Monaco this year."
Alonso will be looking to emulate former US F1 driver Alexander Rossi who won the Indy 500 as a rookie driver in 2016.
For Rossi, who raced five times for the now defunct F1 team Manor Marussia during the 2015 season, winning the Indy 500 has been the highlight of his career.
"I didn't realize the magnitude of [the Indy 500] immediately after I won," he told CNN Sport.
"I'd say I didn't realize it for probably two or three months. I don't think it really fully hit me until the end of the year when I went back to Indianapolis and my face was unveiled on the Borg-Warner Trophy.
"I realized that at that point no one was taking this away and it will be etched in history forever."
McLaren says that an as yet unnamed driver will replace Alonso in Monaco with the Spaniard returning to F1 duties at the Canadian Grand Prix in Montreal on June 11.