Southern Comfort was first produced by Irish bartender Martin Wilkes Heron (1850–1920), the son of a boat-builder. Legend says it was created and sold at McCauley’s Tavern at the corner of Richard and St. Peter Street in the French Quarter of New Orleans, Louisiana. However, St. Peter Street and Richard Street do not intersect, though Richard Street does intersect with S. Peters Street in the Lower Garden District near the Mississippi River. According to the New Orleans Convention & Visitors Bureau, McCauley's Tavern was "just off Bourbon Street," and the original form of the drink was called "Cuffs and Buttons."

Southern Comfort is a fruit, spice and whiskey flavored American liqueur made from neutral spirits and produced since 1874, though not continuously and not always by the modern formula. The brand was created by bartender Martin Wilkes Heron in New Orleans, when he wanted to make a better tasting whiskey. The Brown-Forman Corporation owns the Southern Comfort brand.

Southern Comfort has expanded over the years and has several product offerings globally. Outside the US, Southern Comfort produces single-serve cocktails, including Southern Comfort Lemonade and Lime in the UK and Southern Comfort and Cola in Australia.

Outside of the Americas, Southern Comfort is produced and bottled in Dublin, Ireland.