Comanche production began in 1957 with the PA-24-180 model. The PA-24-250 model was added in 1958, powered by a Lycoming O-540-A1A5 engine. In 1963 the 400 hp (298 kW) PA-24-400 was introduced. The following year, the PA-24-250 was superseded by the PA-24-260, featuring the Lycoming IO-540D or E engine of 260 hp (194 kW). The 260 was also available as the Turbo Comanche C with a Rajay turbocharger and was introduced in 1970.

Production of the Comanche ended when torrential rains from Hurricane Agnes caused the great Susquehanna River flood of 1972, flooding the manufacturing plant and destroying airframes, parts, and much of the tooling necessary for production. Rather than re-build the tooling, Piper chose to abandon production of the Comanche and Twin Comanche, and continue with two newer designs already in production at Piper's other plant in Vero Beach, Florida: the twin engine PA-34 Seneca and the PA-28R-200 Arrow.

At that time Piper had already begun to concentrate on its successful Piper PA-28 Cherokee line, which had originally been conceived as a cheaper alternative to the Comanche. The Arrow was a retractable gear version of the popular Cherokee trainer; its smaller 200 horsepower (150 kW) engine was less expensive and easier to fly than the Comanche; sales of the single engine Comanche had faltered after the introduction of the Arrow in 1967.

The Comanche production run ended with the disposal of all of the tooling, and completion of the last seven airframes. After the Susquehanna River receded, Piper moved the last aircraft to Vero Beach and completed construction there. The self-described junior member of the completion team was Chuck Suma, who 30 years later would become the CEO of The New Piper Aircraft, Inc.