He began his medical career as a surgeon at the Vienna General Hospital and a colleague of Sigmund Freud.

Prior to this discovery, he had tested solutions such as chloral hydrate and morphine as anaesthetics in the eyes of laboratory animals without success.

Freud was fully aware of the pain-killing properties of cocaine, but Koller recognized its tissue-numbing capabilities, and in 1884 demonstrated its potential as a local anaesthetic to the medical community.

In 1888, Karl Koller moved to the United States and practiced ophthalmology in New York.

He received many distinctions in his career, including being honored by the American Ophthalmological Society as the first recipient of the "Lucien Howe Medal" in 1922.