Mayweather, 43-0 with 26 knockouts, will be fighting for the first time since he won a unanimous decision in 12 rounds over Miguel Cotto in May 2012.
Guerrero, 31-1-1 with 18 knockouts, has won 15 straight fights since his most recent loss, a 2005 split-decision against Gamaliel Diaz.
The May 4 fight at the MGM Grand will be televised on Showtime Pay Per View -- part of an overall package that calls for Showtime and its parent company, CBS Corp., to promote as many as six Mayweather fights.
HBO, which has televised 23 Mayweather bouts, issued a statement Tuesday to BoxingScene.com saying it had made "an aggressive and responsible pay-per-view offer."
"Now we move on," HBO said. "We are focused on the best boxing franchise in the television business. We are proud of the roster of superstar fighters and emerging stars who are scheduled to appear on the multiple HBO television platforms this year."
Mayweather, 35, served two months in jail in Clark County, Las Vegas, last year for domestic abuse.