Mark Allison has already run across across the USA and Australia, and is now taking on the 3,400 miles from Lisbon to Istanbul.
The software developer from Bedlington, Northumberland, aims to complete the route across 14 countries in 100 days.
Money raised will go to two charities: the Children's Foundation and the Sir Bobby Robson Foundation.
Mr Allison set off from Tynemouth in the motor home that will be his support base for the duration of the challenge, and will take the ferry from Portsmouth to Santander in Spain on Tuesday.
"This run is a big step up for me in terms of distance and especially elevation," he said.
"I'm looking forward to actually getting started and putting all the preparation into effect.
"But knowing there are 9,000ft climbs like the Stelvio Pass and 15 Tour de France climbs ahead of me is daunting."
Charity fundraiser "Run Geordie Run" has set off for Europe on the next leg of his around the world challenge.