The carrier that has shrunken over the years is being shut down as the company switches to bigger jets.
Comair is down to 290 flights a day. Comair has slashed its fleet, flights and workforce in the last seven years.
Delta told The Associated Press the smaller regional planes are expensive to fly because they are not as fuel-efficient and cost more to maintain.
"We just really couldn't get the cost structure to where we wanted to get it," said Don Bornhorst, senior vice president of Delta Connection and a former Comair president. "It ultimately was a cost issue; it wasn't a quality issue with Comair. They're a good airline, great employees, very innovative ... we just could not solve the cost issues."
Delta confirmed on Friday that it has stopped flying 16 Comair 50-seaters, and will lease the carrier's other 28 planes to other operators.
The employees have been reportedly given a 60-day termination notice. A small group of employees will remain after the Sept. 29 shutdown to handle details of the closure.
Comair handles only about 1 percent of Delta's flying, so the closure won't result in significant changes to Delta's network.
The flight workers are however very upset over the announcement.
"As you can imagine, we're all very sad," said Lynn Dziad, one of the 400 jobless flight attendants.
She celebrated her 22nd anniversary with Comair last week. "It's been a wonderful company. A lot of incredible people have worked here."
Aviation expert Mike Boyd of The Boyd Group said he expected the Comair shutdown, because the regional airline business has no hope.
"It's not going to turn around," Boyd said. "Delta is quite correctly saying 'We've got to get rid of these uneconomic airlines.' "
Comair had more than 7,000 employees and 1,160 flights before they hit bankruptcy in September 2005, Comair and Delta however emerged from bankruptcy reorganization in April 2007.
Before finalizing on the closure, Delta had talked to prospective buyers for Comair, but without success.
It sold its other regional airlines Compass and Mesaba back in 2010, which still operate.