Services on its A320 aircraft to and from the Greek capital will run on Tuesdays and Fridays.
Tom Screen, aviation director for the airport, said after watching the first Athens departure take off: “We are very pleased to welcome back Aegean after a five-year absence.
“Whether customers want to enjoy historic Athens or travel onwards to the popular Greek islands, we are in no doubt that these Aegean services will be well subscribed.
“For customers travelling from Greece, Birmingham, at the heart of the growing West Midlands region, has strong appeal for those travelling on business or leisure.”
Aegean will be the seventh Star Alliance carrier at Birmingham Airport, which pre-pandemic served 12.5 million passengers a year.
It is one of the West Midlands’ largest employers, supporting 30,900 jobs.
In the years to 2033, the airport plans to increase its annual passenger numbers to more than 18m, which will result in jobs supported rising to 34,000.