The 421 was first produced in 1968. It was redesigned in 1970 and marketed as the 421B.

In 1976 the 421C appeared which featured wet wings and the absence of wing tip fuel tanks. In 1980 the 421C's landing gear was changed from straight-leg to a trailing-link design.

Production ended in 1985 due to product liability concerns, along with all other piston-powered Cessna aircraft.

The aircraft remains a popular high-performance pressurized personal aircraft and commands high prices in the used aircraft market.

The prototype 421 took to the skies for the first time in October 1965 (three years after the 411). In comparison to the 411 on which it was based, the 421 introduced a cabin pressurization system, more powerful geared and turbocharged GTSIO-520-D engines and a higher max takeoff weight. Deliveries of production 421s began in May 1967, Cessna at the time claiming it as the cheapest pressurized twin on the market.