Named for Uxbridge, England, a name which was originally derived from "Wixan's Bridge". The Wixan were a 7th-century Saxon tribe from Lincolnshire who also began to settle in what became Middlesex. Anglo-Saxons began to settle and farm in the area of Uxbridge, England in the 5th century, clearing the dense woodland and remaining there for around 500 years.

The first settlers in the area were Quakers who started arriving in 1806 from the Catawissa area of Pennsylvania. The community's oldest building, the Uxbridge Friends Meeting House, was built in 1820 and overlooks the town from Quaker Hill, a kilometre to the west.

The first passenger carrying narrow gauge railway in North America, the Toronto and Nipissing Railway arrived in Uxbridge in June 1871, and for over a decade Uxbridge was the headquarters of the railway. In 1872, the Village of Uxbridge was separated from the Township and incorporated as a separate entity.