Born in Ohio, he worked at Lick Observatory from 1893 to 1909 and then was director of the Argentine National Observatory (today, Observatorio Astronómico de Córdoba) in Argentina from 1909 until 1936.

In 1901, he and George Ritchey observed the apparent superluminal motion in the nebulosity surrounding Nova Persei 1901.

He discovered two moons of Jupiter, today known as Himalia (in 1904) and Elara (in 1905). They were simply designated "Jupiter VI" and "Jupiter VII" and were not given their present names until 1975.

He co-discovered the lost periodic comet 18D / Perrine - Mrkos and several other comets. Antonín Mrkos later named the asteroid 6779 Perrine after him. The lunar crater Perrine is also named after him.

He promoted the study of astrophysics in Argentina and pushed for the construction of a large telescope (the Bosque Alegre telescope), which however was not completed until 1942 (he had retired in 1936). He remained in Argentina after retirement and died there, in Villa General Mitre (which has since been renamed to its original name of Villa del Totoral). He is buried in the cementerio disidente in the city of Córdoba.