The Saudi-based organization, which includes representatives from 57 Muslim countries, said such threats are "very dangerous" and, if initiated, "hundreds of millions of Muslims across the world will be filled with unprecedented rage."
The statement added an attack would also "ignite the fire of extremism that will have serious and direct repercussions on global peace."
Threats by extremist Jewish groups opposing the Israeli withdrawal from Gaza to storm al-Aqsa Mosque, Islam's third holiest shrine, has drawn widespread warnings from Arab and Muslim countries.
The OIC said if al-Aqsa is attacked, the region would be pulled into a new cycle of violence, destroying efforts to restore the peace process.
It called on the U.N. Security Council and other international bodies to to prevent such an attack."
A similar warning was issued by Jordanian Islamic Affairs Minister Abdul Salam Abbadi, who told United Press International his government "condemns all measures that disparage and harm Islamic sites in Jerusalem."
The 1994 Jordan-Israel peace treaty recognized Jordan's guardianship role of the shrines in Jerusalem.