AirLink has resumed limited service between Johannesburg and Cape Town on Level 3 of the coronavirus lockdown, with the flight operated by a 98-seat Embraer E190 regional jet.
It is also offering flights on the Johannesburg-Durban route.
It has joined Mango, FlySafair and Cemair in resuming some domestic flights now that business travel is permitted.
According to Wesgro, the official tourism, trade and investment promotion agency for Cape Town and the Western Cape, the resumed service will be an important business and cargo connection between two major urban centres in South Africa.
AirLink had been showing good passenger growth to the region before the start of the coronavirus (Covid-19) pandemic and resultant flight bans.
The airline saw a 16% increase in passenger growth in 2019, when compared to the previous year, as well as a double-digit compound annual growth rate (CAGR) of 12% between 2016 and 2019.
Tim Harris, CEO of Wesgro, said air access is a significant contributor to tourism globally and a key factor in re-stimulating economic development, which will be crucial for the Western Cape as it continues to recover from the effects of the pandemic.
However, African airlines are forecast to make a total net loss of $2 billion in 2020, according to the International Air Transport Association (IATA).
CEO and managing director of SA AirLink Rodger Foster said while the virus remained a threat, safety protocols were in place and the airline hopes to open up more domestic routes in the near future.
"We wish to assure customers that we have carefully defined and applied our risk mitigation protocols in the interests of the safety of our customers and staff," he said in a statement.
Deon Cloete, general manager of Cape Town International Airport, said it too was ready to welcome passengers for a "safe and seamless" transition, despite additional protocols.
For some other airlines, their fate is still unclear.
Comair, which operates Kulula.com and British Airways domestically under a license agreement, is currently in business rescue and has indicated that it will only consider resuming flights by about November if it is commercially viable and if the company has managed to obtain the necessary funds.
It is as yet uncertain if or when state-owned flag carrier South African Airways, currently in business rescue too, will resume any flights. Before the lockdown flight bans its practitioners had reduced its domestic flights to only the Johannesburg-Cape Town route.
State-owned regional airline SA Express is currently in provisional liquidation and its provisional liquidator has indicated that no resumption of flights is currently foreseen.