Led by Muscat-based British explorer Mark Evans, the three-man team will retrace the 1,300-kilometre (800-mile) route taken by a British civil servant, Bertram Thomas, in 1930, from Salalah in southern Oman, through Saudi Arabia, to Doha in Qatar.
Despite the threat of warring tribes and a constant struggle to find enough water, Thomas completed the journey in 57 days.
Evans, 54, and his two Omani colleagues will be accompanied by two vehicles to carry water and provisions, along with a train of four camels, but will need to stop at the same watering holes Thomas used 85 years ago to top up their supplies.
"It will be a trip that has its difficulties. We're walking across one of the least inhabited places on earth," Evans told AFP as he prepared to set off.
But he said the team would count on the same kind of hospitality that Thomas experienced on the original journey.
"The openness and the warmth and the friendship is the same as it was 85 years ago," Evans said.
"People's misconceptions of this part of the world are pretty wide off the mark.... I feel safer out here than I certainly do back in the UK."
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Evans said the journey was made possible with assistance from the Omani government, which facilitated border crossings into Saudi Arabia and Qatar.
One goal of the expedition is to inspire younger Omanis to take an interest in the sultanate's desert heritage and teach them the values of hard work and perseverance.
It is also an opportunity to highlight Oman's soft diplomacy in a region plagued by insecurity.
Ruled by Sultan Qaboos since 1970, Oman has for decades pursued a foreign policy focused on tolerance and conflict resolution, often acting as a mediator in regional affairs.
Unlike many of its Gulf neighbours, Oman has not joined the Saudi-led coalition battling Shiite rebels in Yemen and has cultivated closer ties with Iran.
"We are all one Arabia, working together to bridge positive aspects of life that we all share," Sayyid Badr bin Hamad Al Busaidi, the secretary general of the Omani foreign ministry, said at a ceremony in Salalah for the start of the expedition.
"This trip is reasserting that message of peace and love, to build cooperation across the whole region for better days to come."