The flotilla was made up of U-boats dispatched from German home ports, which travelled via the Atlantic and the Strait of Gibraltar, and coastal-type UB- and UC-boats, which were moved in segments by rail to Pola and assembled there at the See-Arsenal of the Austro-Hungarian Navy (kaiserliche und königliche Kriegsmarine: k.u.k.).
Due to the favourable conditions for commerce raiding in the Mediterranean, they caused a disproportionately large number of Allied losses during the U-boat campaign.
Eight of the IGN's top dozen U-boat aces served in the Pola flotilla, including Lothar von Arnauld de la Perière and Waldemar Kophamel.
In June 1917, the unit was renamed U-Flottille Mittelmeer and in January 1918 it was divided into two separate Flotillas, the first based at Pola, and the second at Cattaro, while the commander, re-titled (Führer der Unterseeboote im Mittelmeer: U-Boat Leader, Mediterranean) assumed overall command of the forces there and at Constantinople.
One of its boats, SM UB-50 sank the battleship HMS Britannia, the last British warship sunk during the U-Boat Campaign in World War I.