Tusk's comments weighed into a debate in Britain about whether to hold a second referendum on Brexit, following the June 2016 vote to leave.
He won the backing of European Commission chief Jean-Claude Juncker, who urged London to heed the suggestion that it could stay in the bloc.
“If the UK government sticks to its decision to leave, Brexit will become a reality with all its negative consequences in March next year, unless there is a change of heart among our British friends,” Tusk told the European Parliament, to light applause.
“Wasn't it (British Brexit minister) David Davis himself who said if a democracy cannot change its mind it ceases to be a democracy?” he told the assembly in a speech about last month's EU summit.
“We on the continent haven't had a change of heart. Our hearts are still open to you.”
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Leading Brexit campaigner Nigel Farage surprisingly pushed the issue back onto the agenda last week when he said he was increasingly open to the idea of a second referendum.
Former UKIP leader Farage said it would silence those in Britain who do not want to leave the bloc, but it was quickly seized upon by pro-EU politicians.
British Prime Minister Theresa May's spokesman later ruled out a second vote. British voters in 2016 chose to leave the EU by 52 percent to 48 percent.
Juncker however called on the British government to listen to Tusk's suggestion.
“Tusk said our door still remains open and I hope that that will be heard clearly in London,” the former Luxembourg prime minister said.
'I am a dreamer'
It is not the first time the former Polish premier has suggested Britain could change its mind.
In June, Tusk channelled the spirit of late Beatle John Lennon when he said that some of his British friends had asked whether the “impossible” idea of Britain staying in the EU could come true.
“You may say I am a dreamer, but I am not the only one,” he said, quoting Lennon's song “Imagine”.
Tusk meanwhile stressed that the remaining 27 EU states would push ahead with negotiations with Britain on its departure, urging London to say what it wanted in terms of post-Brexit ties.
“What we need today is more clarity on the UK's vision. Once we have that, the leaders will meet and decide on the way that we see the future relationship with the UK as a third country,” Tusk said.
He added that “we must keep the unity of the EU 27 in every scenario”, amid reports that member states are increasingly divided on how tough to be on Britain.
“The hardest work is still ahead of us and time is limited.”
Britain and the EU reached a deal in principle on separation issues in December, and are due to start talks next month on a short transition period after Britain's departure in March 2019.
Talks on future relations — including the all-important issue of a possible trade deal, and how closely Britain will stay allied to the EU's single market and customs union — are not due to start until April.
Brexit will loom in the background when French President Emmanuel Macron goes to Calais later Tuesday to pressure Britain to contribute more to dealing with migrants trying to cross the channel.