Early in 1941, as a result of feedback from Transport Command pilots in Russia, the decision was taken to produce a motorized variant of the Me 321, to be designated Me 323. It was decided to use French Gnome et Rhoné GR14N radial engines rated at 1,180 PS (1,164 hp, 868 kW) for take-off as used in the Bloch MB.175 aircraft; using French engines was thought to place no burden on Germany's overstrained industry.

Initial tests were conducted using four Gnome engines attached to a strengthened Me 321 wing, which gave a modest speed of 210 km/h (130 mph) - 80 km/h (50 mph) slower than the Ju 52 transport aircraft. A fixed indercarriage was fitted, which comprised four small wheels in a bogie at the front of the aircraft with six larger wheels in two lines of three at each side of the fuselage, partly covered by an aerodynamic fairing. The rear wheels were fitted with pneumatic brakes, and could stop the aircraft within 200 m (660 ft).

The four-engined Me 323C was considered merely a stepping stone to the six-engined D series; it still required the five-engined Heinkel He 111Z Zwilling or the highly dangerous Troikaschlepp formation of three Messerschmitt Bf-110 heavy fighter and rocket assisted take-off to get airborne when fully loaded, but it could return to base under its own power when empty. This was clearly not much better than the Me 321, so the V2 prototype became the first to have six engines and flew for the first time in early 1942, becoming the prototype for the D series aircraft.

The selection of the six engines, and their specific placement on the wing's leading edge, were fitted to reduce torque - a trio of counterclockwise rotation engines mounted on the port wing, and a trio of clockwise rotation engines on the starboard wing, resulting in the props rotating "away" from each other at the tops of their arcs, like the counter-rotating twin propellers on the Heinkel He 177 also did.

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