Drug testing had long been a major stumbling block in bringing together the best two pound-for-pound fighters.
However, the pair have consented to rules established under the World Anti-Doping Code and the World Anti-Doping Agency (WADA) banned-substance list.
Both fighters now face unannounced blood and urine testing without reservation and will be tested before and after the MGM Grand showdown.
Some of the banned substances that will be tested for at the WADA-accredited laboratory are growth hormone (HGH), erythropoietin (EPO) and the use of carbon isotope ratio (CIR).
Punishment for a positive test is a four-year suspension.
“It???s a??strong??statement of the importance of clean and safe competition to have these two fighters voluntarily agree to have a WADA level anti-doping program implemented for this fight,” said USADA CEO Travis Tygart.
“We commend them for their stand for clean sport and the message it sends to all those who want to compete clean at the highest levels of all sport.”
Five-division world champion Mayweather had been expected to meet Pacquiao in 2010 until negotiations collapsed over his demand for random drug testing.
Mayweather went on to question how Pacquiao could have won world titles in an unprecedented eight weight classes and was subsequently successfully sued by the Filipino.