It heads northeast along the western edge of some Loess bluffs for several miles to pass through Eden and enter the Hillside National Wildlife Refuge before crossing into Holmes County.

US 49E parallels Tchula Lake as it passes through the Morgan Brake National Wildlife Refuge and Cruger, where it intersects unsigned MS 818.

The highway heads as a four-lane highway to pass through business districts and cross the Yazoo River before leaving Greenwood and US 49E splits off and heads north.

The highway then enters Tutwiler and comes to an end shortly thereafter at a Y-Intersection between US 49, US 49W, and MS 3.

[4] Between Brooklyn and Hattiesburg, travelers had the option of a 24-mile-long (39 km) direct route via US 49W, or a somewhat shorter but broken route on US 49E, serving the Forrest County Agricultural High School and the small community of McLaurin, Mississippi.