Delta Air Lines will add non-stop service between Cleveland and Indianapolis, and Cleveland and Raleigh-Durham from 5 June.
The SkyTeam carrier will operate daily on each route, says the airline.
Raleigh-Durham will be served by Delta Connection carrier ExpressJet with 65-seat Bombardier CRJ700s, while Delta subsidiary Endeavor Air will operate 50-seat Bombardier CRJ200s on the Indianapolis flights.
Delta's new flights come as United Airlines plans to downsize operations at Cleveland in the coming months, dropping the city as a hub. United operates non-stop on both of Delta's new routes, but will cease non-stop service to Raleigh-Durham in April and to Indianapolis in June.