Already operating a 44 strong fleet of A220-300s, airBaltic is currently the largest A220-300 operator in the world. The airline's history with the Airbus A220-300 dates back to 2016 where it was the launch customer, and in 2020, it refreshed its fleet to solely operate this aircraft type.

As of early 2026, Delta Air Lines remains the largest owner and operator of the Airbus A220 family in the world. Delta has a massive fleet consisting of both the A220-100 and the larger A220-300 variants, with over 80 aircraft currently in service and dozens more on order to reach a total of 145. The second-largest operator is JetBlue Airways, which has aggressively transitioned its short-haul fleet to the A220-300 to replace its aging Embraer 190s. In Europe, airBaltic is the most significant operator, famously maintaining an "all-A220" fleet, which has allowed them to become the launch customer for many of the type's technical updates. Air France also holds a substantial and growing fleet of A220s as they phase out their older Airbus A318 and A319 models. The A220 is highly favored by these airlines for its 2-3 seating configuration, larger windows, and significantly lower fuel burn compared to older regional jets.