Route 280, or Highway 280, may refer to:

Australia

• McIvor Highway

Canada

• Manitoba Provincial Road 280
• New Brunswick Route 280

Japan

• Japan National Route 280

United States

• Interstate 280 (multiple highways)
• U.S. Route 280
• Arizona State Route 280 (former)
• Arkansas Highway 280
  • Arkansas Highway 280 Spur
• Florida State Road 280 (former)
• Georgia State Route 280
• Kentucky Route 280
• Maryland Route 280 (former)
• Minnesota State Highway 280
• Montana Secondary Highway 280
• New York State Route 280
• North Carolina Highway 280
• Pennsylvania Route 280 (former)
• South Carolina Highway 280
• Tennessee State Route 280
• Texas State Highway 280 (former proposed)
  • Texas State Highway Spur 280
  • Farm to Market Road 280 (Texas)
• Utah State Route 280