It was an emotional farewell for the crews of the 12 yachts as thousands of people waved them off from the City's quay.
The home crew, the Derry-Londonderry-Doire, sit second overall after finishing runners up in the 12th stage.
It is the last planned visit of the yacht race to the city.
More than 163,000 people are estimated to have enjoyed the nine-day Foyle Maritime Festival and the Clipper events.
It was the third time the race has included Derry as a stopover city.
Deputy First Minister Martin McGuinness said he was confident the event could return in two years time.
"There's such a connection between the city and indeed the region with Clipper that I think it would be a huge mistake on our part not to do everything in our power [to bring it back].
"That doesn't mean there aren't big challenges, there are, of course. It is a very expensive event to host.
"I just think that the argument is so powerful for them to come back to the city that we can't fail."
Mr McGuinness said he had a positive and constructive conversation with the race organisers, but that the event could cost about Â£2m to host in two years.
Clipper race chairman and founder Sir Robin Knox Johnston said this year's stop over had been the best yet.
"It's just enormous and this stop over has got better every time we have come here," he said.
"This has definitely been the best yet given the reception the crew have had here all week, it's been fantastic to see the crowds and support. Frankly, you can't help but enjoy it."
The maritime festival concluded on Saturday evening with an outdoor performance featuring aerial performers, an illuminated flotilla of boats on the Foyle, fireworks and the story of the medieval maritime heroine Sunniva.
Mayor Hilary McClintock said the festival had been a major success for the region.
"It was a sad moment as we waved farewell to the Clipper race fleet today after an eventful week of celebration.
"Once again, we've demonstrated our ability to stage an international event generating substantial revenue for the local economy, and enhancing the region's profile as an exciting and unique visitor destination."
The Clipper Round the World yacht fleet has left Londonderry after the Foyle Maritime Festival came to a close on Sunday.