"The alleged desecration, if it occurred, would be deplorable and completely out of keeping with our deeply held values of religious freedom and tolerance," the department said in a statement.
"Desecration of the Holy Quran is a reprehensible act that would not be sanctioned by the United States for any purpose."
The report in Newsweek magazine touched off protests in Afghanistan which resulted in four deaths and more than 50 injured.
In Pakistan, President Pervez Musharraf's government "expressed its serious concerns to senior officials at our embassy," State Department spokesman Tom Casey said.
"Obviously, the destruction of any kind of holy book, whether it's a Bible or a Quran or any other document like that, is something that's reprehensible and not in keeping with US policies and practices," Casey said in a briefing.
Rights groups have denounced
the Guantanamo detentions
The allegations are "certainly serious, and it would be important to have them be looked into".
Newsweek reported that in order to rattle suspects, US interrogators placed Qurans on toilets and in at least one case "flushed a holy book down the toilet".
Casey said he was certain that the US military will "treat any kind of violations of religious rights of detainees very seriously".
Later, in the written statement, the State Department confirmed the Pakistani complaint and said: "All credible allegations of maltreatment or abuse of detainees at Guantanamo are reported and investigated.
"If these allegations prove to be substantiated, the perpetrators of abuses will be held accountable."