The first example was completed by mid-1940. Power was supposed to be supplied by two 24-cylinder Jumo 222 six-bank, four cylinders per bank, hyper engine output class powerplants, but problems with 222 development meant the first prototypes flew with BMW 801 radial engines, instead. The first flight-quality 222s did not arrive until October 1941, and even at this point it was clear they were nowhere near ready for full-scale production. When it became apparent the 222 was not likely to become a viable powerplant, in May 1942, Junkers proposed replacing them with the much heavier Daimler Benz DB 606s instead.
As these technical difficulties were being addressed, the lack of a strategic bombing doctrine within the Luftwaffe meant the mission and purpose of the Ju 288 remained nebulous throughout its development. As an interim measure, RLM ordered the Junkers Ju 188, which was a fairly minor upgrade of the original Ju 88 incorporating the basic cockpit design of the never-produced Ju 88B. Work continued on the 288 throughout, but in 1944 the project was finally abandoned as Luftwaffe priorities became more intensely focused on homeland defense.