| State: | MO |
| Type: | Route |
| Route: | 221 |
| Maint: | MoDOT |
| Map Custom: | yes |
| Map Notes: | MO 221 highlighted in red |
| Length Mi: | 16.317 |
| Direction A: | West |
| Terminus A: | near Pilot Knob |
| Direction B: | East |
| Terminus B: | near Farmington |
| Previous Type: | Route |
| Previous Route: | 215 |
| Next Type: | Route |
| Next Route: | 224 |
| Counties: | Iron, St. Francois |
Route 221 is a 16.317adj=midNaNadj=mid east–west highway in eastern Missouri. Its western terminus is at Route 21 near Pilot Knob. Its eastern terminus is at U.S. Route 67 (US 67) near Farmington.