Middendorf's was opened in 1934 during the Great Depression by a German couple named Josie and Louis Middendorf. The restaurant was passed down through two generations of the family. In September 2006, a year after Hurricane Katrina, the Lamonte family, the then second generation owners, sold the restaurant to German born chef, Horst Pfeifer, and his wife, Karen. The Pfeifers had just lost their five star New Orleans restaurant, Bella Luna, to the winds from the hurricane and from subsequent looting. Since purchasing the restaurant, the Pfeiefers have preserved the traditional menu, which includes a mixture of three distinct cuisines: Creole, Cajun, and Southern. Its most famous dish is the thin fried catfish, which Southern Living magazine has declared, "Possibly the best fried fish in the world.

Middendorf's is located 40 miles northwest of New Orleans near Manchac. To the south of Middendorf's is Pass Manchac, a seven-mile-long serpentining natural canal that connects lakes Maurepas and Pontchartrain. On the north side is the Amite River. The two lakes and two rivers form the boundaries for the hourglass-shaped island named Jones Island.