The following highways are numbered 221:

• Manitoba Provincial Road 221
• Newfoundland and Labrador Route 221
• Nova Scotia Route 221
• Prince Edward Island Route 221
• Quebec Route 221
• Saskatchewan Highway 221

• China National Highway 221

• Santa Clara–Sagua Road (4–221)

• National Route 221

• Japan National Route 221

• A221 road
• B221 road

• U.S. Route 221
• Alabama State Route 221
• Arkansas Highway 221
• California State Route 221
• Florida State Road 221 (former)
• Georgia State Route 221 (former)
• Iowa Highway 221 (former)
• K-221 (Kansas highway) (former)
• Kentucky Route 221
• Maine State Route 221
• Minnesota State Highway 221 (former)
• Montana Secondary Highway 221
• Nevada State Route 221
• New Mexico State Road 221
• New York State Route 221
• Ohio State Route 221
• Oregon Route 221
• Pennsylvania Route 221
• Tennessee State Route 221
• Texas State Highway 221 (former)
  • Texas State Highway Loop 221 (former)
• Utah State Route 221 (former)
• Washington State Route 221
• Wyoming Highway 221