The name is believed to be a diminutive form of muffe ('mold', 'mushroom'), perhaps due to the round sandwich bread being reminiscent of a mushroom cap; or from muffola, 'muff', 'mitten'.

Depending on the specific Sicilian dialect, the item may be spelled: The muffuletta is somewhat similar to the pan bagnat sandwich of Nice, France.

[13] The muffuletta sandwich is said to have been created in 1906 at Central Grocery Co. on Decatur Street, New Orleans, Louisiana, U.S., by its delicatessen owner Salvatore Lupo, a Sicilian immigrant.

[14][15] Sicilian immigrant Biaggio Montalbano, who was a delicatessen owner in New Orleans, is credited with invention of the Roma Sandwich, which may have been a forerunner of the muffuletta.

[17] The traditional-style muffuletta sandwich consists of a muffuletta loaf[18] split horizontally and covered with layers of marinated muffuletta-style olive salad,[19] salami, ham, Swiss cheese, provolone, and mortadella.