From the confluence of these two waterways, the main branch flows roughly due east past Two Dot, Harlowton, and Roundup, then turns north just past Melstone, and continues to the UL Bend on the Missouri River at the beginning of Fort Peck Reservoir.

The river is about 100 feet (30 m) wide in its last 90 miles (140 km), with increased choppiness and flow rate.

The relatively more arid climate in this section results in less vegetation, more livestock grazing, and poorer soil.

Species of fish found on the North and/or South Forks down to Harlowton include: mountain whitefish, and brown, cutthroat, rainbow, and brook trout.

The eastern part of the river has channel catfish, sauger, smallmouth bass, and walleye due to the warmer water caused by dewatering from irrigation and the arid climate shift from mountain to prairie ecosystems in the Musselshell's last 90 miles (140 km).

[15] Cresting and flow rate records were set along several sections of the river, such as Mosby and Shawmut, near Harlowton.

Zoologist William Temple Hornaday of the Smithsonian Institution harvested specimens from the region in 1886 so that future generations would know what the buffalo looked like.

[20] Roundup is home to the Musselshell Valley Historical Museum, which documents the region's history.