The son of the portrait painter Jonathan Trego, William Trego was born in Yardley, Bucks County, Pennsylvania. At the age of two, he was stricken with paralysis, probably due to polio. In spite of this handicap, Trego went on to become a noted painter of military subjects. When William was sixteen, the family moved to Detroit, where the elder Trego established a studio at which William studied.

William's career was launched when the twenty-year old artist exhibited and sold his painting titled "The Charge of Custer at Winchester" at the Michigan State Fair. With the proceeds from the sale, he moved to Philadelphia to attend the Pennsylvania Academy of the Fine Arts and study under Thomas Eakins. He won the first Toppan Prize in 1882 at the Academy, and in 1883 was the top entrant for the Temple Competition. Trego was teacher and mentor to Walter Baum.

In 1887 Trego set sail for Paris, where he took classes from Tony Robert-Fleury and William Adolphe Bouguereau at the Academy Julian. He exhibited battle subjects at the Paris Salon in 1889 and 1890. Back in Philadelphia in 1890, Trego was hailed as "the American Detaille" for his many military paintings.

From about 1886 until he died in 1909, William Trego lived in North Wales and painted in the studio then behind his home. The fields near his home in that era served as background for many paintings and he often used North Wales residents and horses as models for his battle scenes and other works during that period.