It rises about 1 mile (1.6 km) east of Chipping Norton, and flows southeast past Old Chalford, Enstone, Kiddington, Glympton and Wootton, Woodstock and through Blenheim Park.
At Wootton the Glyme is joined by a tributary, the River Dorn.
The Glyme joins the Evenlode just south of the park near Bladon.
The Glyme is dammed at Cleveley, Kiddington, Glympton and Blenheim.
The upper part of the Glyme Valley around the river's headwaters is a Site of Special Scientific Interest.