The river begins at an unnamed lake, about 50 kilometres (31 mi) northeast of Ogoki Post (Marten Falls First Nation) and adjacent to the Streatfeild River drainage basin, and first heads north, then east, then southeast to Kapiskau Lake.

It continues southeast and then east before turning north to take in the right tributary Noluskatsi River.

It continues northeast, takes in the right tributary Otadaonanis River just before the river mouth, then reaches its mouth at James Bay.

[2][3] Portions of the headwaters of the Kapiskau River and its tributaries lie within the southeastern edge of the Northern Ontario Ring of Fire.

[4] The James Bay Winter Road that connects Moosonee and Attawapiskat crosses the Kapiskau River.