| 1 | MDW to SJU San Juan, United States | 2,059 mi | 4h 50m | Southwest Airlines | 2×/wk |
| 2 | MDW to PUJ Punta Cana, Dominican Republic | 1,968 mi | 4h 39m | Southwest Airlines | 1/day |
| 3 | MDW to SFO San Francisco, United States | 1,850 mi | 4h 24m | Southwest Airlines and Delta Air Lines | 2-3/day |
| 4 | MDW to OAK Oakland, United States | 1,840 mi | 4h 23m | Southwest Airlines | 2-3/day |
| 5 | MDW to SJC San Jose, United States | 1,833 mi | 4h 22m | Southwest Airlines | 2-3/day |
| 6 | MDW to SBA Santa Barbara, United States | 1,805 mi | 4h 18m | VJA | weekly |
| 7 | MDW to SMF Sacramento, United States | 1,786 mi | 4h 16m | Southwest Airlines | 2-3/day |
| 8 | MDW to LAX Los Angeles, United States | 1,747 mi | 4h 11m | Southwest Airlines | 3-4/day |
| 9 | MDW to PDX Portland, United States | 1,747 mi | 4h 11m | Southwest Airlines | 2-3/day |
| 10 | MDW to LGB Long Beach, United States | 1,738 mi | 4h 10m | Southwest Airlines | 1/day |
| 11 | MDW to BUR Burbank, United States | 1,736 mi | 4h 10m | Southwest Airlines | 1/day |
| 12 | MDW to SEA Seattle, United States | 1,729 mi | 4h 9m | Southwest Airlines | 3/day |
| 13 | MDW to GDL Guadalajara, Mexico | 1,727 mi | 4h 9m | Volaris | 1/day |
| 14 | MDW to NZY San Diego, United States | 1,727 mi | 4h 9m | Southwest Airlines | weekly |
| 15 | MDW to SAN San Diego, United States | 1,725 mi | 4h 9m | Southwest Airlines | 3-4/day |
| 16 | MDW to CLD Carlsbad, United States | 1,716 mi | 4h 7m | WDY | weekly |
| 17 | MDW to MBJ Montego Bay, Jamaica | 1,710 mi | 4h 7m | Southwest Airlines | 2×/wk |
| 18 | MDW to MLM Morelia, Mexico | 1,703 mi | 4h 6m | Volaris | 1/day |
| 19 | MDW to ONT Ontario, United States | 1,702 mi | 4h 6m | Southwest Airlines | 1/day |
| 20 | MDW to RNO Reno, United States | 1,676 mi | 4h 3m | Southwest Airlines | 1/day |
| 21 | MDW to BJX Silao, Mexico | 1,644 mi | 3h 59m | Volaris | 3×/wk |
| 22 | MDW to AGU Aguascalientes, Mexico | 1,625 mi | 3h 56m | Volaris | 1/day |
| 23 | MDW to ZCL Zacatecas, Mexico | 1,564 mi | 3h 49m | Volaris | 1/day |
| 24 | MDW to DGO Durango, Mexico | 1,554 mi | 3h 47m | Volaris | 3×/wk |
| 25 | MDW to SLP San Luis Potosi, Mexico | 1,550 mi | 3h 47m | Volaris | 1/day |