Fascinated by flight since childhood, Cayley conducted a variety of tests and experiments intended to explore aerodynamic principles and to gather information of value in the design of aircraft. He published the results of his original research in 1809. His most important discoveries included the advantages of streamlining, the means of obtaining longitudinal and lateral stability, elements of wing design, thoughts on biplane and multiplane wings, and the use of rudders and elevators for control. Throughout his active career, Cayley designed a variety of aircraft, including helicopters (helicopter), airships, and fixed-wing machines.

Cayley established the modern configuration of an airplane as a fixed-wing flying machine with separate systems for lift, propulsion, and control as early as 1799 (see Silver Disc machine). In 1804 he flew the first successful glider model of which there is any record. His work culminated in 1853 with the completion of a full-scale glider that carried his reluctant coachman on the first manned glider flight on record.

An individual of wide technical and scientific interests, Cayley invented the light-tension wheel (forerunner of the bicycle wheel), the expansion-air, or hot-air, engine (1805), and the caterpillar tractor (1825). He was a founder of the Regent Street Polytechnic Institution (charter of incorporation granted in 1839; now the Royal Polytechnic Institution). He also pursued research in science education, land reclamation, acoustics, railway equipment, lifeboats (lifeboat), ballistics, optics, and electricity.