It is joined by a tributary off of Bear lake, then turns southwest and enters the township of Seguin, flows through Upper Fry Lake and Lower Fry Lake and passes north over a series of waterfalls near the community of Seguin Falls, at which point it is crossed by the former path of the Ottawa, Arnprior and Parry Sound Railway, now the recreational Seguin Trail rail trail.

The Seguin continues through Mountain Chute to reach Mill Lake in the town of Parry Sound, where it takes in the left tributary Haines Creek, heads under Ontario Highway 400 then over Mill Lake Dam,[2] and takes in the right tributary Darlington's Creek.

It then flows under a low bridge carrying the Canadian National Railway main line, over the Cascade Street Dam and Cascade Street Generating Station,[2] over the Trestle Dam,[2] under the high Parry Sound CPR Trestle that carries the Canadian Pacific Railway, and reaches its mouth at Parry Sound.

[2] A sawmill built at the mouth of the river in 1857 was one of the first industries in the area, and which later led to the founding of the town of Parry Sound.

It protects upland forest, steep cliff and metavolcanic bedrock outcropping landscapes.