Brazil’s anti-trust authorities said they approved the merger of the Brazilian airline TAM with Chile’s LAN, first proposed in 2010.
The new airline, LATAM, is valued at about $14.5bn (£9.4bn) and will represent 6% of global air transport.
Last year, TAM and LAN flew more than 45 million passengers and 754,777 tonnes of cargo.
The combined airline would fly to 115 destinations in 23 countries, with a 40,000-strong workforce.
Chile’s anti-trust authorities had already approved the merger but had set 11 conditions, including fewer flights to the Peruvian capital, Lima.
Brazil’s body also set some conditions, including a reduction in the number of flights between Sao Paulo and Santiago and that the two airlines join a single international body.
TAM is a member of the Star Alliance group of airlines, which includes BMI, Lufthansa, SAS and Air China.
Meanwhile LAN is a member of the Oneworld airline alliance, which includes Iberia, British Airways, Qantas and JAL.
The airlines have not yet said which one they will join.