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The singer completed her international farewell tour in 2005 but will now star in a new show at the 4,100-seat Colosseum.
She will perform four concerts a week for a month from May 6, then alternate with Bette Midler from August until October. Her agreement with promoter AEG Live is said to be worth £30 million.
The 61-year-old told ABC's Nightline: "I know it's a lot, but I don't care. If it's a lot, if someone says, 'ooh, it's a lot', OK. Fine. It must be a lot."
She promised that the show will be "visually unbelievable", saying: "Our set moves down from the ceiling, in from the sides, up from the floor. We have screens in the foreground, the centre and the back. We can change a city into a forest in two seconds. You'll see a different stage for every song."
Cher will replace Celine Dion, who completed her five-year residency at Caesars Palace in December.
