Dave Heeley, from West Bromwich, hopes to raise Â£30,000 by running 160 miles through the Sahara Desert in the Marathon des Sables.
Mr Heeley, who set off at 08:00 BST, described the trip as "the adventure of a lifetime".
He is raising funds for the Albion Foundation who said Mr Heeley was "unbelievable".
Mr Heeley, who is known as "Blind Dave", has completed several gruelling challenges in the past few years.
In 2008 he ran seven marathons in seven days on seven continents, while in 2011 he ran 10 marathons in 10 days - travelling from John O'Groats to Land's End and cycling between each stage.
He said the Marathon des Sables, which is run in Morocco through the Sahara Desert in temperatures of about 37C, was the "biggest thing" he had ever done.
"It's the adventure of a lifetime," he said.
Rob Lake, director of the Albion Foundation, the charitable arm of West Bromwich Albion football club which provides educational and sporting opportunities to young people, said: "The guy is unbelievable".
"It's a phenomenal task he is taking on," he added.
So far, Mr Heeley said he had raised Â£20,000.
A blind man who ran seven marathons in seven days on seven continents has embarked on a new charity challenge.