Almost all of Upton State Forest is within the Blackstone River Watershed.  The Blackstone River Watershed is located in south central Massachusetts and includes portions of the northeastern corner of Rhode Island. The Blackstone River, named for the first European resident of the Valley, Reverend William Blaxton, originates in the hills of Worcester and flows 48 miles south into Rhode Island, emptying into the Narragansett Bay near Providence, Rhode Island.

The West River has three sub watersheds in Upton: Miscoe Brook, Warren Brook, and Center Brook.   The upper reaches of Miscoe Brook are located in Grafton and Westborough, north of the Massachusetts Turnpike. Miscoe Brook flows southerly through Lake Wildwood until it joins Warren Brook where the two brooks combine to form the West River.  Warren Brook originates in northern Upton with several unnamed tributaries.  These include tributaries which originate within or near Upton State Forest near Westborough Road.

The upper reaches of the Center Brook watershed are in Upton State Forest.  The major headwater stream is Anderson Brook which flows from Dean Pond to Pratt Pond.  Center Brook originates at Pratt Pond and joins the West River near Mendon Street.