The 757 was produced in two fuselage lengths. The original 757-200 entered service in 1983; the 757-200PF, a package freighter (PF) variant, and the 757-200M, a passenger-freighter combi model, debuted in the late 1980s.

The 757-200, the original version of the aircraft, entered service in 1983. The type was produced with two different door configurations, both with three standard cabin doors per side: the baseline version has a fourth, smaller cabin door on each side aft of the wings, and is certified for a maximum capacity of 239, while the alternate version has a pair of over-the-wing emergency exits on each side, and can seat a maximum of 224.

The 757-200 was offered with a MTOW of up to 255,000 pounds (116,000 kg); some airlines and publications have referred to higher gross weight versions with ETOPS certification as “757-200ERs”,  but this designation is not used by the manufacturer.Similarly, versions with winglets are sometimes called “757-200W” or “757-200WL”.

Although designed for short and medium length routes, the 757-200 has since been used in a variety of roles ranging from high-frequency shuttle services to transatlantic routes. In 1992, after gaining ETOPS approval, American Trans Air launched 757-200 transpacific services between Tucson and Honolulu. Since the turn of the century, mainline U.S. carriers have increasingly deployed the type on transatlantic routes to Europe, and particularly to smaller cities where passenger volumes are insufficient for wide-body aircraft.

Production for the 757-200 totaled 913 aircraft, making the type by far the most popular 757 model.

The narrow-body twinjet succeeded earlier single-aisle airliners, and became commonly used for short and mid-range domestic routes, shuttle services, and transcontinental U.S. flights. After regulators granted approval for extended flights over water (ETOPS) in 1986, airlines also began using the aircraft for intercontinental routes.

Production of the 757 ended in October 2004, after 1,050 had been built for 54 customers. The 757-200 was by far the most popular model, with 913 built. Diminished sales amid an airline industry trend toward smaller jetliners led Boeing to end production without a direct replacement, in favor of the 737 family. The last 757 was delivered in November 2005. In July 2017, 666 of the narrow-body twinjets were in airline service.

Aircraft of similar role, configuration and era are: Airbus A321, Boeing 737-900ER, Boeing Business Jet, Tupolev Tu-204.