In the middle of the Second World War, the Army Air Force felt the need of an aircraft which will be faster than the contemporary aircrafts and will carry heavy loads of conventional weapons in farther distance. B-29D at that time was in operation but could not meet these requirements.

As World War II ended, the production of B-29s was suspended. Only the B-29D, in the series, survived but its overall role changed. In December 1945, these B-29Ds were re-designated as the B-50 and was assigned for the important atomic role. 

The Army Air Force wanted replacements of both B-36 and B-29s, though both of these aircrafts by than were modified to carry atomic bombs. The short-ranged B-50 was recognized as a temporary solution. The B-29D featured many changes before turning in into B-50. The re-designated aircraft, built with a stronger but lighter grade of aluminum, had larger flaps, a higher vertical tail, a hydraulic rudder boost, nose wheel steering, a efficient undercarriage retracting mechanism, and a new electrical device to remove the ice from the pilot's windows. The new aircraft's wings and empennage also could be thermally de-iced. Also, the four higher-thrust Pratt & Whitney R-4360 engines that replaced the standard B-29's R-3350s; gave a power increase of 59 percent, and electrically controlled, reversible pitch propellers allowed the use of engine power as an aid to braking on short or wet runways.  

The new B-50 had some limitations as well. The limitations included its small space and engine malfunctions. Quick development of special heavy weapons of that time created more complications. Another problem it had was the cracking of the metal skin on the trailing edge of the wings and flaps dictated extensive modifications. To make things worse, fuel tank overflows, leaking fuel check valves, troubles in engine turbo-chargers and generator defects were revealed. Moreover, most B-50s came off the production lines without the receiver end of the new air-to-air refueling system being developed by Boeing. 

The B-50 was assigned the Boeing factory designation of Model 345-2. The first B-50 to be built was a ‘production article’ rather than a prototype. The first production version was designated as B-50A, reflecting the new Air Force policy of assigning the A series suffix to the first production model of a new series. The B-50 was originally to have been built at Renton, but a change in plans resulted in a shift of manufacture to Seattle Plant 2. The first B-50A flew on June 25, 1947. In total, 59, B-50As were built as standard bombers. The 60th aircraft was stored in the factory for modification as the YB-50C, which was intended as a prototype for the B-54A series, an improved version of the B-50. 

The first B-50As were delivered in June of 1948 to the Strategic Air Command's 43rd Bombardment Wing, based at Davis-Monthan AFB in Arizona. This wing was assigned the mission of being the primary carrier of the atomic bomb. 

After one B-50A had crashed in Alaska, engineers found that the congealing of oil in the small-sized tubing of the aircraft's manifold pressure regulator did not work properly. It was then modified. There were numerous engine malfunctions, and the constant speed drive alternators were found defective. 

Boeing built 371 of B-50s between 1947 and 1953, some of those served the active inventory until 1965. An aerial refueling tanker conversion designated KB-50 was used in the Vietnam War. The reconnaissance variant, the RB-50B existed and played an important role in Cold War spying. B-50 was grounded and completely removed from the active inventory when wreckage of a KB-50 broke up in flight in 1965 due to corrosion problems in the fleet.

The B-50B was externally identical to the B-50A, with all the differences being internal. The aircraft had an increase in the gross weight from 168,480 pounds to 170,400 pounds and was equipped with a new type of lightweight fuel cell. The B-50B introduced a new wrinkle into the production block number system. Instead of starting the block numbers over at -1 for the new series, the B-50B block numbers simply continued on from where the B-50A blocks had ended. Consequently, the first B-50B was B-50B-40 and continued on to -60. Subsequent B-50s continued this practice. Leaks from the new light-weight fuel cells were an unexpected problem. Very early in the production run of the B-50B, these leaky cells had to be replaced by a new type of fuel cell. Pending the availability of new cells, deliveries of new B-50Ds were actually stopped.

The B-50C was an advanced version of the B-50 which was designed to squeeze the maximum amount of performance that could possibly be gotten from the basic Superfortress design. The B-50C was powered by four new R-4360-43 turbo-compound engines. The change to turbo compound engines required a complete redesign of the airframe, with a wider wingspan and a longer fuselage. The takeoff weight of the B-50C was estimated to be 207,000 pounds, almost 50,000 pounds greater than that of most other B-50s.

The B-50D was the most-produced version of the B-50 series. A total of 222 B-50Ds were built by the manufacturer. The B-50D was primarily intended as a stopgap nuclear-capable medium bomber, pending the availability of the B-47. The B-50D marked a major change in the B-50 series, which justified a new factory designation of Model 345-9-6. The most noticeable outward change introduced by the B-50D was a revised nose with a single large molded one-piece plastic cone and an optically-flat bomb-aimer's window in the lower portion which replaced the seven-piece B-29 unit that was used through the B-50B. The first B-50D took off on its maiden flight in May of 1949. Deliveries to SAC began in late June of 1949. The first outfits to receive the B-50D were the 93rd and 509th Bombardment Wings. The last of 222 B-50Ds was delivered in December of 1950. Some of SAC's 5 wings of atomic-capable B-50Ds began to exchange their aircraft for B-47s in late 1953. 

On October 20, 1955, the last B-50D of the 97th Bombardment Wing phased out of the active nuclear force. The retired B-50Ds were then reconfigured for other roles such as aerial refueling tanker, weather reconnaissance, and training. These modified aircraft remained in USAF service for another ten years.

The four-engine, propeller-powered Boeing B-50 bomber was among the last piston-powered bombers built during an era that was to be dominated by jets. No flying examples exist today, although several can be found in various air museums across the country.