The maiden direct flight of national carrier RwandAir from Kigali to Tel Aviv, Israel's economic and technology hub, took off on Monday night.
Tel Aviv will be the airline's 29th destination overall, and second in the Middle East, after United Arab Emirates.
Rwandair will fly to Tel Aviv three times a week from Kigali and the new route will be operated on Tuesdays, Thursdays and Saturdays by Boeing 737-800NG.
It will be offering 16 seats in business class and 138 seats in economy class, according to the airline's officials.
The development will, among other things, strengthen ties between the two friendly nations as well as boost business.
Yvonne Manzi Makolo, RwandAir's chief executive, said that adding Tel Aviv to the airline's network is part of their long-term plan to link Rwanda to the rest of the world.
"Tel Aviv is one of the world's leading tech hubs and we look forward to flying business travellers as well as pilgrims visiting the Holy Land, to and from our network on this new route," she said.
She added: "It will also be a great opportunity to ease travel and strengthen diplomatic ties between the two countries."
The route is also expected to be important as it will connect regional travellers, especially from Africa, to the Middle Eastern country.
"We don't look at passengers from Rwanda alone," Makolo said in an interview on Monday.
RwandAir has in recent years been opening new routes as it seeks to reach previously un-served and underserved markets, which has had multiple impacts on Rwanda's economy, including boosting the hospitality industry.
In April, the airline launched flights to DR Congo's capital, Kinshasa, and last week it launched flights to the Chinese commercial hub of Guangzhou.