From July 1863 until June 1864, he was acting assistant surgeon in the U. S. Army, after which he entered private practice in Brooklyn and advanced to become Professor of Disease of Women at Long Island College Hospital.

He performed the first successful operation of gastro-elytrotomy that is recorded, and also that of craniotomy, using Sims's speculum.

Primarily, he is remembered for his description of the Skene's glands at the floor of the urethra.

Skene collaborated with J. Marion Sims, who performed gynecologic exams and surgeries on enslaved African-American women without anesthesia, but Skene does not appear to be part of these experiments.

[3] As a sculptor, Skene created a bust of Sims which is on display in the lobby of the Kings County Medical Society.