The river is formed in South-central Worcester, Massachusetts, by the confluence of the Middle River and Mill Brook. From there, it follows a rough southeast course past Worcester City and Northbridge. It then flows through Millbury, Sutton, Grafton, Northbridge, Uxbridge, Millville, and Blackstone.
It continues into Rhode Island, flowing past Woonsocket, Cumberland, Lincoln, Central Falls, and Pawtucket, where it then reaches Pawtucket Falls. Following this, the river becomes tidal and flows into the Seekonk River just north of Providence.
Other tributaries join the Blackstone along the way, such as the West River and Mumford River in Uxbridge, Massachusetts; and the Branch River, in North Smithfield, Rhode Island.
