Gold was discovered along the river near the end of the 19th century and several mining operations established in the area.

The river turns southwest into Rainy River District, heads over the Long Rapids and Camp Six Rapids, takes in the left tributary Mercutio River, tumbles over the Islands Falls, reaches Bradshaw Lake and flows into the Marmion Lake and reservoir, where it takes in four right tributaries.

According to Barnes, the Upper Seine River was a "prime gold area."

This lake is controlled at the west end by the Sturgeon Falls Dam and generating station (8 MW), also built in 1926 and also operated today by Abitibi-Consolidated Hydro.

[3][4] The river heads west, is crossed by Ontario Highway 11, passes the community of Seine River Village (post office established in 1895 on the right bank,[5] and reaches its mouth at Seine Bay on Rainy Lake.