The former undisputed world heavyweight champion said the combination of Mayweather's boxing experience and hand speed will be too much to handle for McGregor, who has made him name as a mixed martial arts fighter.
"It's ridiculous to me," Lewis told US sports broadcaster ESPN. "You are talking about one discipline where you can use only your hands and only a few can do it.
"Every battle sport always starts with your hands, but they are two totally different sports."
"I can't take it serious," Lewis said. "Mayweather is the best in his weight class, no one can touch him in boxing.
"Floyd will stop him. He's just too good at boxing for McGregor and McGregor is just too inexperienced.
"I wouldn't buy it -- but I would be interested in the result. To me, I know who is going to win already so there's no use in watching it."
The 40-year-old Mayweather has been retired since beating Andre Berto in September 2015 and improving his career record to 49-0.
The matchup with McGregor gives Mayweather a chance to reach the 50-0 career milestone.
Former champ Oscar De La Hoya and promoter Kathy Duva have also slammed the event as an exhibition spectacle, pointing to the fact that the 28-year-old McGregor has never had a professional boxing match and only dabbled in the sport as a teenager.
"I don't believe it would damage boxing .... I love Bruce Lee and the other disciplines and when he fought against other fighters, you wanted to see the differences, so I can see the appeal," Lewis said.
Mayweather-McGregor have yet to get together face-to-face since the announcement but they are expected to announce a promotional tour that will take them to a couple of major US cities.
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