Lufthansa requested a new design that would replace the Ju 52, but offer much greater loads, seating, range and performance.

Junkers responded with the EF.77 design with a pressurized fuselage with seating for up to 35, making it one of the larger airliners in the world at that time.

It was powered by three Junkers Jumo 211F engines, in nacelles almost identical in appearance, each complete with annular radiator and possibly as Kraftei unitized "power-egg" modular engine installations, to those on Jumo 211-powered versions of the Junkers Ju 88, replacing the BMW 132 of the Ju 52, which dramatically improved performance.

Like earlier tail-dragger designs, the Ju 252 would normally be difficult to load when parked, owing to the sloping floor.

Junkers had already pioneered - with the earlier Junkers Ju 90's fifth and sixth prototype airframes during 1939 - a unique solution to this problem, the Trapoklappe, a hydraulically powered ventral rear loading ramp that possessed powerful enough operating mechanisms to lift the plane off its tailwheel, leveling the floor and allowing oversized cargo to be loaded directly forward into the fuselage.