Design work on the Jumo 222 started in 1937. The engine consisted of six engine blocks with four cylinders each, arranged around the central crankshaft. The engine looked like a radial due to the arrangement, but the internal workings were more like a V-engine, and it was liquid cooled. The cylinders were arranged such that neighbouring banks had exhaust and intakes beside each other, resulting in simpler "piping" from the rear-mounted supercharger and resulting in only three sets of exhausts. Each cylinder had two intake valves and a single sodium-cooled exhaust, a high-pressure fuel injector between the intakes, and two spark plugs. With a bore and stroke of 135 mm, the engine had a displacement of 46.5 litres. It was forced to run at a fairly low 6.5 compression ratio, the best possible given the low-octane fuels available in Germany, but by increasing the speed of the engine to 3,200 rpm, the 222 delivered 2,500 hp (1,850 kW) at takeoff. The only disappointing feature was the simp le one-stage two-speed supercharger, but even with this limitation the engine still generated 2,200 hp at 16,400 ft. The dry weight was 1088 kg.

Compared to the contemporary BMW 801 and Daimler-Benz DB 605, the 222 was a huge leap in performance. It had only slightly larger displacement than the 801's 41.5 l, and about 1/4 more than the 605's 35.7 l, but delivered considerably more power, 2,500 hp (1,850 kW) compared to 1,600 hp (1,193 kW) in the 801 and 1,500 hp (1,119 kW) in the 605. That represents 40 kW/L for the 222, while only 29 kW/L for the 801, and 31 kW/L for the 605. Even more impressively the power to weight ratio was 1.04 hp/lb (1.7 kW/kg) for the 222, whereas the 605 delivered an otherwise excellent 0.88 hp/lb (1.4 kW/kg), and the 801 a fairly poor 0.60 hp/lb (1 kW/kg). The 222 was also about the same size as these smaller engines, 1.16 m across compared to 1.27 m for the 801, and 2.4 m long compared to 2.3 m for the 605. The comparison was even more favourable against other high-power engines under development. The DB 606 consisted of two DB 601's bolted together that delivered 2,400 hp (1,790 kW) from a whoppin g 3,340 lb (1,515 kg), and was 2.1 x 1.6 x 1.1 m in size. The RLM was excited by the possibilities of the design, and the similar DB 604.

The first prototype engine ran on April, 24th 1939, and was later air-tested on the nose-engine mount of a Junkers Ju 52. Production called for two primary models, the 222A and 222B, which differed only in the direction that they spun, intended to be used for left and right-hand engines on twin-engine designs. However, continued testing went poorly, and Junkers eventually decided it was best to stop development of these "Series I" engines and move onto a modified "Series II". The new 222A-2 and B-2 ran at a slightly slower rpm but had slightly larger cylinders of 140mm bore for the same net performance, while the A-3 and B-3 used a different supercharger for better performance at higher altitudes. Both continued to prove unreliable, and were fitted only experimentally.

By late 1941 Junkers decided the best course of action was to make more radical changes to the design, and introduced the 222C and 222D models. With a new bore and stroke of 145x140 mm, the engine displacement increased to 49.9 litres. Back at the original 3,200 rpm the C/D models could deliver just under 3,000 hp (2,200 kW) when they started running in the summer of 1942. However the problems were not cured, and only a handful were built. The RLM had been waiting for three years at this point, and eventually gave up and had all designs based on it look for alternate engines. Later that year they gave up on that as well, and cancelled the entire Bomber B program outright.

Junkers still didn't give up. Using the original A/B design they added a new two-stage supercharger including an aftercooler for high-altitude use, resulting in the 222E and F-series. Although sea-level performance was unchanged, the engine was producing 1,930 hp at 29,500 ft. By this point it appeared that the problems were finally being worked out, but bombing of the Dessau factories made production almost impossible. A final attempt for even higher altitude performance resulted in the turbocharged 222G and H, built only to the extent of a few testbed prototypes.

The Jumo 222 was a massive and very costly failure. 289 222's were built in total, none to see active service. It also served to seriously hamper Luftwaffe designs from 1940 to 1942, when everyone waited for the 222 to finally start working. Meanwhile all calls for four-engine adaptations in place of two-engine 222 powered designs were rejected because it was felt it would place too much strain on the German engine industry. In the end there was nothing to show for it, and late in the war the Luftwaffe was flying barely-updated versions of their original pre-war designs.