Midgley joined the Dayton Engineering Laboratories Company (Delco), a subsidiary of General Motors (GM), to address the problem of engine knocking in automobiles. This marked the beginning of his research into antiknock additives.

Midgley and his team systematically tested numerous chemical compounds to find an effective anti-knocking agent. Initially, they focused on organic compounds of ethanol and other readily available chemicals.

After extensive research, Midgley discovered that tetraethyllead (TEL) was a highly effective anti-knocking agent. Adding a small amount of TEL to gasoline significantly reduced engine knocking and improved engine performance.

General Motors, in partnership with Standard Oil, established the Ethyl Gasoline Corporation to produce and market gasoline containing TEL. This marked the widespread introduction of leaded gasoline to the public.

Early reports of lead poisoning among workers at TEL production facilities raised concerns about the safety of leaded gasoline. Midgley publicly defended TEL, even staging a demonstration where he inhaled TEL vapor to showcase its supposed safety.

Midgley took a leave of absence from work to recover from lead poisoning he contracted while working with TEL. This incident was downplayed publicly by GM and Ethyl Corporation.