Beyond negative economic implications, a Brexit would trigger "first and foremost geopolitical" consequences, Tusk told German mass circulation daily Bild in an interview.
"Do you know why these consequences are so dangerous? Because in the long-term they are completely unpredictable," he said.
"As a historian, I am afraid this could in fact be the start of the process of the destruction of not only the EU but also of Western political civilisation," Tusk said.
The process of dissolving all contractual ties between the bloc and Britain would itself already take two years, he said.
Also Read
And more time would have to be factored in before a new relationship could be agreed upon, he said.
"Every single one of the 27 member states as well as the European parliament would have to approve the overall result. That would take at least five years, and I'm afraid, without any guarantee of success," added Tusk.