The highway is also the subject of songs by Big Joe Williams and Howlin' Wolf (Chester Arthur Burnett).

[2] Today, it is the only four-laned route directly connecting Jackson, the state's capital and largest city, to the Mississippi Gulf Coast.

At this point, travelers have an option of continuing on US 49 through Hattiesburg or using the I-59/US 98 bypass which reconnects with US 49 in the northern part of the city.

US 49 passes Hattiesburg's primary medical facility, Forrest General Hospital, and the campus of the University of Southern Mississippi before arriving at another, more standard cloverleaf interchange with I-59.

It is also at I-59, where Mississippi Highway 42 (MS 42) runs with US 49 for a short distance as suburban development is soon encountered as the road returns to rural environs.

Eventually, MS 42 departs from the four-laned highway and branches off to the west toward smaller towns, starting with Sumrall.

I-20/I-55/US 49 crosses the Pearl River into Hinds County and bypasses Downtown Jackson, where I-55 departs to the south.

A split in the highway, rare in the U.S. Highway System, begins here; both routes head into the Mississippi Delta, US 49W serving the towns of Belzoni and Indianola, where it junctions with US 82 and its four-lane segment ends, while two-laned US 49E serves Tchula before encountering US 82 at Greenwood.

It is at Clarksdale that US 49 encounters "The Crossroads", the legendary junction with State Street (an old alignment of US 61) where the great blues musician Robert Johnson is reputed to have sold his soul to the devil.

US 49 Business runs around the north part of the city, with the main route meeting AR 242 in the southern portion.

The two routes angle north through downtown Jonesboro, crossing US 63 Business and passing by ASU Stadium before leaving town.

U.S. Route 49W (US 49W) is an 81.89-mile-long (131.79 km) U.S. Highway in the Delta Region of Mississippi, passing through Yazoo, Humphreys, Sunflower, and Tallahatchie counties.