The 1980–81 Midland Football Combination season was the 44th in the history of Midland Football Combination, a football competition in England.
| Competition: | Midland Football Combination Division One |
| Season: | 1980–81 |
| Winners: | Moor Green |
| Matches: | 380 |
| Total Goals: | 1114 |
| Prevseason: | 1979–80 |
| Nextseason: | 1981–82 |
Division One featured 18 clubs which competed in the division last season along with two new clubs, promoted from Division Two: