Route 81 or Highway 81 may refer to:

International

• AH81 Asian Highway 81
• E81 European route E81

Australia

• Escort Way (New South Wales)
• Mulligan Highway and Peninsula Developmental Road – Queensland State Route 81
• (Victoria)

Canada

• Newfoundland and Labrador Route 81

India

• National Highway 81 (India)

Korea, South

• National Route 81

Mexico

• Mexican Federal Highway 81

Philippines

• N81 highway (Philippines)

United States

• Interstate 81
  • Interstate 81E (former)
  • Interstate 81S (former)
• U.S. Route 81
• Alabama State Route 81
• Arizona State Route 81 (former)
• Arkansas Highway 81
• California State Route 81
• Connecticut Route 81
• Florida State Road 81
  • County Road 81A (Holmes County, Florida)
• Georgia State Route 81
• Idaho State Highway 81
• Illinois Route 81
• Iowa Highway 81
• Kentucky Route 81
• Louisiana Highway 81
  • Louisiana State Route 81 (former)
• Maryland Route 81 (former)
• Massachusetts Route 81
• M-81 (Michigan highway)
• Minnesota:
  • Minnesota State Highway 81 (1934)
  • Minnesota State Highway 81 (pre-1988)
• Missouri Route 81
• Montana Highway 81
• Nebraska Highway 81 (former)
• Nevada State Route 81 (former)
• New Jersey Route 81
  • County Route 81 (Bergen County, New Jersey)
• New Mexico State Road 81
• New York State Route 81
  • County Route 81A (Cayuga County, New York)
    • County Route 81C (Cayuga County, New York)
  • County Route 81 (Chautauqua County, New York)
  • County Route 81 (Dutchess County, New York)
  • County Route 81 (Essex County, New York)
  • County Route 81 (Madison County, New York)
  • County Route 81 (Montgomery County, New York)
  • County Route 81 (Oneida County, New York)
  • County Route 81 (Rockland County, New York)
  • County Route 81 (Suffolk County, New York)
  • County Route 81 (Sullivan County, New York)
• North Carolina Highway 81
• Country Road 81 (Richland County, North Dakota)
• Ohio State Route 81
• Oklahoma State Highway 81A
• Pennsylvania Route 81 (former)
• Rhode Island Route 81
• South Carolina Highway 81
• South Dakota Highway 81 (former)
• Tennessee State Route 81
  • Tennessee State Route 81A (former)
• Texas State Highway 81
  • Texas State Highway Loop 81 (former)
  • Farm to Market Road 81
• Utah State Route 81
• Virginia State Route 81 (former)
• West Virginia Route 81 (1925–1941) (former)
  • West Virginia Route 81 (1960–1961) (former)
• Wisconsin Highway 81

Territories

• U.S. Virgin Islands Highway 81