Flights will initially operate four times a week when they recommence on 3 December.
The resumption ends a spell in which the airline has not served London since 17 January 2021 after restrictions were put in place between the UK and Brazil due to the pandemic.
Sao Paulo is mainly a business destination, but it is also Brazil’s main hub with numerous connections. Latam will offer economy return fares from £507, with flights departing Heathrow at 20.35, arriving 05.20 the next day.
Joao Murias, Latam Airlines regional commercial director, said: "We are proud to reconnect London to Sao Paulo, and from there to all of South America.
“The demand as soon as the news broke that we were back in operation has been incredible, which reinforces that our commitment to connecting the UK to South America is more topical than ever".
