While the 757 program had been financially successful, declining sales in the early 2000s threatened its continued viability. Airlines were again gravitating toward smaller aircraft, now mainly the 737 and A320, because of their reduced financial risk.

The Boeing 757 was officially discontinued in 2004 primarily due to shifting market dynamics and the evolution of newer, more fuel-efficient aircraft. During the late 1990s and early 2000s, airlines began favoring smaller, more economical narrow-body planes like the Boeing 737 Next Generation and the Airbus A321 for shorter routes, while long-haul "thin" routes were increasingly handled by smaller wide-body jets. The 757 was a "niche" aircraft: it had incredible power and "short-field" performance (allowing it to take off from short runways in high-altitude or hot climates), but its heavy airframe and older engine technology made it more expensive to operate as fuel prices rose. Furthermore, the post-9/11 downturn in aviation led to a slump in orders for mid-sized jets. In 2026, many 757s are still in service as cargo freighters or for specialized long-haul missions, but the Airbus A321XLR has effectively become its spiritual successor, offering the same transcontinental range with significantly lower fuel burn and modern avionics, making the original 757's high-power, high-cost design obsolete for modern commercial fleets.