The river is named for the Buffalo fish which was abundant when the first European settlers arrived.

The highway crosses the North Fork several times as it parallels the river for about 3 miles (5 km).

The confluence of the North and South forks about a mile west of Highway 43 is the head of the Buffalo.

The confluence with the Little Buffalo River occurs in Lewis County followed by smaller tributaries.

State Route 99 parallels the river for a distance and then crosses it in the broad Texas Bottoms.

Entering northern Wayne County, the stream has several more tributaries, notably the Green River.

Here State Route 13 bridges the Buffalo and then abruptly turns northerly for the balance of its flow.

Shortly after crossing into Humphreys County, it is bridged by Interstate 40 and then by Bakerville Road.

Impoundments include 349 lake acres in ponds and water stored behind 10 dams.

The non-aquatic species include 18 plants, one mammal, three birds, two reptiles, one amphibian, three insects and spiders, and one other invertebrate.

Both the Cracking Pearly Mussel and the Pale Lilliput are listed by both State and Federal authorities as Endangered.

[6]: 13–14 Except for a very small section on the southern end, the watershed is part of the Western Highland Rim, one of 25 Level IV subecoregions in the state.

The Mississippian limestone base along with chert and shale is overlaid by fairly thin soils of moderate fertility.

Much of the differential erosion leading to the terrain features results from differences in deposition and mineralization of the various types of limestone in the area and the presence of large portions of chert.

Some chert bears small quantities of the iron-containing mineral hematite or other oxides of iron.

The Middle Tennessee Council of the Boy Scouts of America operates Grimes Canoe Base along the Buffalo in southern Perry County.