| 1 | BUF to LAX Los Angeles, United States | 2,213 mi | 5h 9m | JetBlue Airways | 1/day |
| 2 | BUF to LAS Las Vegas, United States | 1,982 mi | 4h 40m | Southwest Airlines | weekly |
| 3 | BUF to PHX Phoenix, United States | 1,908 mi | 4h 31m | Southwest Airlines | weekly |
| 4 | BUF to SJU San Juan, United States | 1,849 mi | 4h 24m | JetBlue Airways | 1/day |
| 5 | BUF to DEN Denver, United States | 1,356 mi | 3h 23m | Southwest Airlines and United Airlines | 2-3/day |
| 6 | BUF to IAH Houston, United States | 1,281 mi | 3h 14m | American Airlines | weekly |
| 7 | BUF to DFW Dallas, United States | 1,211 mi | 3h 5m | American Airlines | 1-2/day |
| 8 | BUF to DAL Dallas, United States | 1,205 mi | 3h 4m | Southwest Airlines | 2×/wk |
| 9 | BUF to FLL Fort Lauderdale, United States | 1,168 mi | 3h | JetBlue Airways | 1/day |
| 10 | BUF to RSW Fort Myers, United States | 1,146 mi | 2h 57m | JetBlue Airways | 3×/wk |
| 11 | BUF to TPA Tampa, United States | 1,056 mi | 2h 46m | Southwest Airlines | 1/day |
| 12 | BUF to TUL Tulsa, United States | 1,023 mi | 2h 42m | American Airlines | weekly |
| 13 | BUF to MCO Orlando, United States | 1,013 mi | 2h 40m | Southwest Airlines, JetBlue Airways, and Frontier Airlines | 3-4/day |
| 14 | BUF to JAX Jacksonville, United States | 875 mi | 2h 23m | American Airlines | weekly |
| 15 | BUF to MEM Memphis, United States | 813 mi | 2h 16m | United Airlines | weekly |
| 16 | BUF to BRD Brainerd, United States | 792 mi | 2h 13m | AirShare LLC | weekly |
| 17 | BUF to MSP Minneapolis, United States | 733 mi | 2h 6m | Delta Air Lines and Sun Country Airlines | 1-2/day |
| 18 | BUF to ATL Atlanta, United States | 713 mi | 2h 3m | Delta Air Lines and Frontier Airlines | 4-5/day |
| 19 | BUF to CHA Chattanooga, United States | 647 mi | 1h 55m | American Airlines | weekly |
| 20 | BUF to BNA Nashville, United States | 633 mi | 1h 53m | Southwest Airlines | 1-2/day |
| 21 | BUF to CLT Charlotte, United States | 547 mi | 1h 43m | American Airlines, AirShare LLC, and Frontier Airlines | 3-4/day |
| 22 | BUF to RDU Raleigh, United States | 488 mi | 1h 35m | Frontier Airlines | 3×/wk |
| 23 | BUF to ORD Chicago, United States | 472 mi | 1h 33m | United Airlines, American Airlines, and Delta Air Lines | 7-8/day |
| 24 | BUF to MDW Chicago, United States | 467 mi | 1h 33m | Southwest Airlines | 2-3/day |
| 25 | BUF to MKE Milwaukee, United States | 463 mi | 1h 32m | American Airlines | weekly |