The headwaters of the river rise on the north-eastern section of the Barkly Tableland in the Northern Territory,[4] in an area of gently undulating downs country dominated by cattle stations.

The river is fed by springs in shallow valleys[5] and it then flows eastwards through an area of well-developed canyons in Queensland.

The Gregory discharges into the Nicholson River to the southwest of Burketown, having descended 252 metres (827 ft) over its 321-kilometre (199 mi) course.

[2] In March 2023, over 500 mm of rain fell across an already wet catchment in 48 hours, leading to record flooding.

[7][8] The river is surrounded by forested areas on the upper reaches, with riparian woodlands and open savannah on the plains.