[5] About one mile (1.6 km) later, MS 161 intersects Ford Road and enters the city limits of Mound Bayou.

Inside the city, the road (now known as Edwards Avenue) is the boundary of the Mound Bayou Historical District from South Street to Martin Luther King Jr.

[8] MS 161 also passes by the John F. Kennedy Memorial High School and crosses the waterway known as Mound Bayou near Lampard Street.

[3][4] Before US 61 was relocated to a four-lane divided highway, the two-lane road had stop signs and low speed limits that significantly slowed through traffic.

Known as South State Street, MS 161 continues northeastward towards a commercial area of Clarksdale,[14] and it crosses the Sunflower River.

The road name changes to North State Street, and it intersects Desoto Avenue, which travels to downtown Clarksdale northbound and US 49 southbound.

[15] The intersection is home to the "Crossroads" sign, a sculpture that commemorates the alleged location where musician Robert Johnson sold his soul to the devil to learn how to play the blues.

MS 161 starts at US 61 inside the city limits of Walls, and it travels along a two-lane road northeastward through a rural area.