The city of Duquesne was settled in 1789 and incorporated in 1891. The city derives its name from Fort Duquesne.

Duquesne Works, a productive steel mill that was part of Carnegie Steel Corporation and later part of U.S. Steel, was the heart and soul of Duquesne during its brightest moments in the early 20th century. Duquesne was home to the largest blast furnace in the world, named the "Dorothy Six". Bob Dylan's song Duquesne Whistle (Tempest, 2012) is dedicated to it.

The city's population peaked in 1930, then declined with the Great Depression and deindustrialization beginning after World War II. Today a stark post-industrial landscape, Duquesne has fewer total residents (5,565 at the 2010 U.S. census) than were the city's mill workers in 1948. According to the McKeesport Daily News, Duquesne has the worst performing schools in the state of Pennsylvania. Duquesne was designated a financially distressed municipality in 1991 by the state.

The population was 5,254 at the 2020 census.