The B-52E was a slightly improved version of the B-52D. The E model was virtually identical to the D in outward appearance. Most of the improvements were to internal systems. A new bomb navigation system and an improved Doppler radar system were the major avionics upgrades.

The first of 100 B-52Es ordered was completed in October 1957. The first flight was on the roll out date, in part, because the E model was so similar to the D, there was no need for an extensive ground test program. Boeing and the USAF also used the concurrent rollout/first flight for public relations purposes.

Initial deployment of the B-52E in late 1957 was to the 6th Bomb Wing stationed at Walker Air Force Base. Improvements in surface-to-air missile technology during the late 1950s made high-level penetration of enemy airspace increasingly dangerous. Because of this threat, B-52 combat tactics began to change from high-level penetration missions to standoff weapons delivery.

The AGM-28 Hound Dog missile was the primary air-to-ground missile used beginning in the late 1950s. Two AGM-28s were carried on wing pylons mounted between the fuselage and inboard engine nacelles. The B-52E remained in operational frontline service until the early 1970s when the last aircraft were phased out in favor of more modern models.