PTFE was accidentally invented by Roy Plunkett of Kinetic Chemicals in 1938. While Plunkett was attempting to make a new CFC refrigerant, the perfluorethylene polymerized in its pressurized storage container. Kinetic Chemicals patented it in 1941 and registered the Teflon trademark in 1944.

Teflon was first sold commercially in 1946. By 1950, DuPont had acquired full interest in Kinetic Chemicals and was producing over a million pounds (450 t) per year in Parkersburg, West Virginia. In 1954, French engineer Marc Grégoire created the first pan coated with Teflon non-stick resin under the brandname of Tefal after his wife urged him to try the material that he'd been using on fishing tackle on her cooking pans. In the United States, Kansas City, Missouri resident Marion A. Trozzolo, who had been using the substance on scientific utensils, marketed the first frying pan, "The Happy Pan," in 1961

An early advanced use was in the Manhattan Project as a material to coat valves and seals in the pipes holding highly reactive uranium hexafluoride in the vast uranium enrichment plant at Oak Ridge, Tennessee, when it was known as K-25.