The virgin flight, an SA Airlink service from South Africa, ends the island's long-standing reliance on a ship which sailed every three weeks.
It is hoped that the service, funded by the UK, will boost tourism and help make St Helena more self-sufficient.
But British media have dubbed it "the most useless airport in the world".
Built with £285m ($380m) of funding from the UK Department for International Development (Dfid), the airport should have opened in 2016, but dangerous wind conditions delayed the launch.
After further trials this summer, the weekly service between Johannesburg and St Helena was passed as safe.
St Helena had for decades been one of the world's most inaccessible locations, served only by a rare ship service from South Africa.
It is chiefly known as the island to which French Emperor Napoleon Bonaparte was exiled after his defeat in the Battle of Waterloo in 1815, and where died.
