The 'Yele Haiti' singer accused the actor of not noticing the good work he has been doing in the earthquake stricken country because he was too busy taking illegal drugs.
He said: "I got a message for Sean Penn - maybe he ain't see me in Haiti because he was too busy sniffing cocaine."
Although both stars have been heavily involved in aid work in Haiti since its capital, Port Au Prince, was hit by an earthquake which claimed 230,000 lives in January, a bitter war of words has broken out between the pair after Wyclef announced his intentions to run for president of the country in August.
Hitting out at him, Sean said he felt Wyclef's campaign was "about a vision of flying around the world, talking to people".
He later said: "As an ambassador at large, he has been virtually silent."
He also wrote in a newspaper column: "None among us felt or expressed anger toward it, but rather a universal sadness for his silence, as he is America's most admired cultural link to Haiti."
Sean has also quickly refuted Wyclef's outburst, calling it "highly irresponsible and false."
A spokesperson for the actor, Mara Buxbaum, said in a statement: "Mr. Jean is clearly unfamiliar with the physical demands put upon volunteers in Haiti. As aid workers there, the notion of depleting the body's immune system thru the use of illicit drugs is ludicrous.
"More specifically, J/P Haitian Relief Organization (a.k.a. JPHRO) has a ZERO tolerance policy for any and all illegal drugs.
"As the leader of this organisation, Sean Penn has not only set this policy, but adheres to it. That Mr. Jean would make such a false accusation is reckless and saddening, but not surprising."
A few weeks after announcing his plans to run for president of Haiti, the country's electoral officials declared the singer was ineligible to run.
A reason wasn't given for the disqualification, but it is thought to be because the singer had not lived in Haiti for five years, a requirement for candidacy.
