Jenney designed the Home Insurance Company Building, Chicago (1884–85; enlarged 1891; demolished 1931), generally considered to be the world's first tall building supported by an internal frame, or skeleton, of iron and steel rather than by load-bearing walls and the first to incorporate steel as a structural material. The Home Insurance Company Building also set the pace for the Chicago School, many of whose chief exponents—including Louis Sullivan, Daniel Burnham, John Root, and William Holabird—served at one time in Jenney's office.

After studying architecture in Paris (1859–61), Jenney served in the American Civil War (1861–65) as an engineering officer. Having left the Federal army with the rank of major, he practiced engineering and architecture in Chicago (1868–1905) and taught architecture at the University of Michigan, Ann Arbor (1876–80).

In Jenney's design for the Leiter Building, Chicago (1879; enlarged 1888; later demolished), he made a tentative approach to skeleton construction, and the facade was prophetic of the glass curtain wall that became common in the 20th century. Among his other buildings in Chicago are the Manhattan Building (1889–90), said to be the first 16-story structure in the world and the first in which wind bracing was a principal aspect of the design; the Ludington Building (1891); the Fair Store (1891–92; later remodelled as the Loop store of Montgomery Ward); and the second Leiter Building (1889–90), which became Sears, Roebuck and Co.'s Loop store.