With the 23 June referendum fast approaching, Tusk played down claims by some in Vote Leave that a new deal with the EU could be struck quickly as negotiations take place over a new relationship.
He told Bild, the German daily, "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."
In a separate interview with the German Der Spiegel magazine, Tusk said, "In is in. Out is out. I hope and believe that the British will ultimately decide against Brexit. The withdrawal of Britain would be a heavy loss for Europe."
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In another attempt to boost the fortunes of the Remain side, Germany's finance minister, Wolfgang Schäuble, has slammed the door on Britain retaining access to the single market if it votes to the leave.
In an interview in a Brexit-themed issue of Der Spiegel, he ruled out the possibility of the UK following a Swiss or Norwegian model that would allow it to enjoy the benefits of the single market without being an EU member.
"That won't work. It would require the country to abide by the rules of a club from which it currently wants to withdraw."
The two interventions by Tusk and Schäuble come with polls suggesting the result of the referendum will be close, and voters still keen to understand what the practicalities would be if Britain left.
Meanwhile, the UK Labour party on Monday put itself at the forefront of the Remain campaign with its shadow chancellor John McDonnell saying the party wanted to make a "positive case" to remain and reform the EU.
"From Labour's proposals to increase funding to the UK or the tax transparency enforcement programme to clamp down on tax avoidance, Labour wants to better use the EU's levers of power to help British families get more control against the growing economic forces of globalisation.
"The truth is that Tory Brexit comes at a cost to working people, and this risk is not worth taking when we can remain and reform the EU to unlock Labour investment via Europe to create jobs and growth here in the UK.
"Britain should already be leading in Europe with this kind of agenda, and under the next Labour government we will be."
Also speaking on Monday, his colleague, Hilary Benn, Labour's shadow foreign secretary, added, "Labour has a positive vision for change in Europe which the EU needs to embrace once this referendum is over.
"Change to boost living standards and guarantee workers' rights, and working more closely together to ensure our security."
Elsewhere, former MEP Stanley Johnson - father of former London mayor Boris Johnson who strongly advocates leaving the EU - says he will vote for the UK to stay in the EU.
But Johnson, a former Commission official, told a Brussels news website that the EU should scrap the single currency and do more to control immigration if Britain votes to remain.