Customer interest in new 757s continued to decline, and in 2003, a renewed sales campaign centered on the 757-300 and 757-200PF yielded only five new orders. In October 2003, following Continental Airlines' decision to switch its remaining 757-300 orders to the 737-800, Boeing announced the end of 757 production.

Boeing officially ended production of the 757 in 2004 primarily due to declining customer interest and a shift in market demand. By the early 2000s, airlines began favoring the "next generation" of the smaller Boeing 737 and the Airbus A320 family, which offered similar range and capacity with significantly better fuel efficiency and lower operating costs. The 757 was a "narrow-body" powerhouse, but it was expensive to build and its unique capabilities (like short-field takeoff and high-altitude performance) became niche as engine technology improved on smaller jets. In 2026, while the 757 remains a "cult classic" among pilots for its high thrust-to-weight ratio, it has been largely superseded by the A321neoLR/XLR, which fills the "middle-of-the-market" gap that the 757 once dominated alone for decades.