Main Street Historic District or Old Main Street Historic District may refer to the following places in the United States:
- Main Street Historic District (Tuskegee, Alabama), listed on the National Register of Historic Places (NRHP) in Macon County
- Main Street Historic District (Bristol, Connecticut), listed on the NRHP in Hartford County
- Main Street Historic District (Cromwell, Connecticut), listed on the NRHP
- Main Street Historic District (Danbury, Connecticut), listed on the NRHP
- Main Street Historic District (Durham, Connecticut), listed on the NRHP in Middlesex County
- Main Street Historic District (Manchester, Connecticut), listed on the NRHP in Hartford County
- Main Street Historic District (Middletown, Connecticut), listed on the NRHP
- Main Street Historic District (Willimantic, Connecticut), in the town of Windham, Connecticut, listed on the NRHP
- Main Street Historic District (Tampico, Illinois), listed on the NRHP
- Old Main Street Historic District (Dubuque, Iowa), listed on the NRHP in Dubuque County
- Main Street Historic District (Murray, Kentucky), listed on the NRHP in Calloway County
- Main Street Historic District (Baton Rouge, Louisiana), listed on the NRHP
- Main Street Historic District (Broussard, Louisiana), listed on the NRHP
- Main Street Historic District (Auburn, Maine), listed on the NRHP
- Main Street Historic District (Damariscotta, Maine), listed on the NRHP in Lincoln County
- Main Street Historic District (Fryeburg, Maine), listed on the NRHP in Oxford County
- Main Street Historic District (Rockland, Maine), listed on the NRHP in Knox County
- Main Street Historic District (Easthampton, Massachusetts), listed on the NRHP
- Main Street Historic District (Greenfield, Massachusetts), listed on the NRHP
- Main Street Historic District (Haverhill, Massachusetts), listed on the NRHP
- Main Street Historic District (Millville, Massachusetts), listed on the NRHP
- Main Street Historic District (Stockbridge, Massachusetts), listed on the NRHP
- Main Street Historic District (Webster, Massachusetts), listed on the NRHP
- Main Street Historic District (Flushing, Michigan), listed on the NRHP
- Main Street Historic District (Menominee, Michigan), designated Michigan State Historic Site; listed on the NRHP as the "First Street Historic District."
- Main Street Historic District (Milan, Michigan), listed on the NRHP in Washtenaw County
- Main Street Historic District (Bay St. Louis, Mississippi), listed on the NRHP in Hancock County
- Main Street Historic District (Vicksburg, Mississippi), listed on the NRHP in Warren County
- Main Street Historic District (Bozeman, Montana), listed on the NRHP in Gallatin County
- Main Street Historic District (Miles City, Montana), listed on the NRHP
- Main Street Historic District (Red Cloud, Nebraska), listed on the NRHP in Webster County
- Main Street Historic District (Addison, New York), listed on the NRHP
- Main Street Historic District (Afton, New York), listed on the NRHP in Chenango County
- Main Street Historic District (Brockport, New York), listed on the NRHP
- Main Street Historic District (Cold Spring Harbor, New York), listed on the NRHP in Suffolk County
- Main Street Historic District (Cuba, New York), listed on the NRHP in New York
- Main Street Historic District (Geneseo, New York), listed on the NRHP in New York
- Main Street Historic District (McGraw, New York), listed on the NRHP in Cortland County
- Main Street Historic District (Medina, New York), listed on the NRHP in New York
- Main Street Historic District (Millerton, New York), listed on the listed on the NRHP in Dutchess County
- Main Street Historic District (New Hamburg, New York), listed on the NRHP in New York
- Main Street Historic District (Roslyn, New York), listed on the NRHP in New York
- Main Street Historic District (Roxbury, New York), listed on the NRHP in Delaware County
- Main Street Historic District (Stone Ridge, New York), listed on the NRHP in New York
- Main Street Historic District (Whitehall, New York), listed on the NRHP in Washington County
- Main Street Historic District (Brevard, North Carolina), listed on the NRHP in Transylvania County
- Main Street Historic District (Forest City, North Carolina), listed on the NRHP in Rutherford County
- Main Street Historic District (Hendersonville, North Carolina), listed on the NRHP in Henderson County
- Main Street Historic District (Marion, North Carolina), listed on the NRHP in North Carolina
- Main Street Historic District (Rutherfordton, North Carolina), listed on the NRHP in Rutherford County
- Main Street Historic District (Bowling Green, Ohio), listed on the NRHP in Wood County
- Main Street Historic District (Genoa, Ohio), listed on the NRHP in Ottawa County
- Main Street Historic District (Spring Valley, Ohio), listed on the NRHP in Greene County
- Main Street Historic District (Westerly, Rhode Island), listed on the NRHP in Rhode Island
- Main Street Historic District (Woonsocket, Rhode Island), listed on the NRHP in Rhode Island
- Main Street Historic District (Newberry, South Carolina), listed on the NRHP in Newberry County
- Main Street Historic District (Chappell Hill, Texas), listed on the NRHP in Washington County
- Main Street Historic District (Darlington, Wisconsin), listed on the NRHP in Lafayette County
- Main Street Historic District (Fort Atkinson), listed on the NRHP in Wisconsin
- Main Street Historic District (Lake Geneva, Wisconsin), listed on the NRHP in Walworth County
- Main Street Historic District (Mayville, Wisconsin), listed on the NRHP in Dodge County
- Main Street Historic District (Menomonee Falls, Wisconsin), listed on the NRHP in Waukesha County
- Old Main Street Historic District (Racine, Wisconsin), National Register of Historic Places listings in Racine County
- Main Street Historic District (Thiensville, Wisconsin), listed on the NRHP in Ozaukee County
- Main Street Historic District (Trempealeau, Wisconsin), listed on the NRHP in Trempealeau County
- Main Street Historic District (Waupaca, Wisconsin), listed on the NRHP in Waupaca County
- Main Street Historic District (Whitewater, Wisconsin), listed on the NRHP in Walworth County
- Mathias Mitchell Public Square–Main Street Historic District, listed on the NRHP in Portage County, Wisconsin
- Main Street Historic District (Buffalo, Wyoming), listed on the NRHP in Johnson County