Jet2.com’s 6.30am flight to Menorca was the first to depart the expanded facility, with Tui set to resume operations there on Thursday (15 July).
Manchester airport said the project was the "centrepiece" of its £1 billion transformation programme, which got under way in 2017 but was delayed by more than a year due to the Covid pandemic.
The new-look terminal features new shops, cafes, bars and restaurants, a modernised security area and refreshed departure lounge, and will be able to accommodate more passengers.
Karen Smart, managing director of Manchester airport, said as travel restrictions continue to be eased, the airport would be making further announcements on more carriers’ operations out of Terminal Two.
She described Wednesday’s opening as a "hugely significant milestone" for the airport, Manchester, the north of England – and the "wider recovery of the travel industry".
"After a hugely challenging 16 months, we are delighted to be delivering some positive news and welcoming the first passengers into our new terminal extension," said Smart.
Jet2.com and Jet2holidays chief executive Steve Heapy added: "From today [Wednesday], all of our flights will depart and arrive from the expanded Terminal Two, with the exception of arrivals from Jersey."