In an interview with German newspaper Bild, Tusk said a so-called Brexit vote would provide a major boost to radical anti-European forces who he said would be "drinking champagne," as reported by Reuters.
"Why is it so dangerous? Because no one can foresee what the long-term consequences would be," Tusk said. "As a historian, I fear that Brexit could be the beginning of the destruction of not only the EU but also of western political civilization in its entirety."
Read alsoBloomberg: Brexit campaign shifts focus to immigration in attack on CameronEveryone in the European Union would lose out economically if Britain left, Tusk said.
"Every family knows that a divorce is traumatic for everyone. Everyone in the EU, but especially the Brits themselves, would lose out economically," he said.
The latest polls show Britons are almost evenly split over whether to stay or go.
Although he expressed hope that the EU would survive in the event of a Brexit, Tusk said the price would be high.