He is known for work on the enumerative geometry of conic sections, algebraic surfaces, and history of mathematics.

After returning to Copenhagen, Zeuthen submitted his doctoral dissertation on a new method to determine the characteristics of conic systems in 1865.

In 1871 he was appointed as an extraordinary professor at the University of Copenhagen, as well as becoming an editor of Matematisk Tidsskrift, a position he held for 18 years.

For 39 years he served as secretary of the Royal Danish Academy of Sciences and Letters, during which he also lectured at the Polytechnic Institute.

After 1875 Zeuthen began to make contributions in other areas such as mechanics and algebraic geometry, as well as being recognised as an expert on the history of medieval and Greek mathematics.