MS 161 starts at US 61 and US 278, south of the town of Merigold. After intersecting Merigold–Drew Road, the road travels north into the town, where it is known as Second Street. The route crosses over the Jones Bayou past South Street and intersects several streets inside Merigold before exiting city limits near Lee Street. It passes through a small tract of farmland and intersects South Lane Road. About later, MS 161 intersects Ford Road and enters the city limits of Mound Bayou. Inside the city, the road is the boundary of the Mound Bayou Historical District from South Street to Martin Luther King Jr. Street. The Taborian Hospital is also located on the route, outside the historic district. MS 161 also passes by the John F. Kennedy Memorial High School and crosses the waterway known as Mound Bayou near Lampard Street. The route leaves the city near Mohawk Street, and it crosses northwesterly over US 61 and US 278. Past US 61 and US 278, the route intersects Moody Road, the closest connector to US 61 and US 278. The road enters Winstonville at Winston Street, crosses Mount Bayou near Bruce Street, and it leaves the town at Mack Williams Street. Near Tarsi Road, the route turns north and enters Shelby as Broadway Street. MS 161 travels through the residential area of Shelby, and downtown Shelby near Fourth Avenue. The route intersects MS 32 at Second Avenue and travels northward through the town. The road exits the city limits past Blue Cain Road, and it turns eastward past the intersection. MS 161 ends at a three-way junction with US 61 and US 278 north of Shelby. In 2000, US 61 was rerouted between Merigold and Shelby, and its old alignment became MS 161. 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. ;Major intersections
Clarksdale–Lyon
MS 161 starts at an intersection with US 61, US 278, and MS 322 in Clarksdale. The route travels northeast, concurrent to MS 322, across several farms before reaching Sherard Road, where MS 322 continues westward to Sherard. Known as South State Street, MS 161 continues northeastward towards a commercial area of Clarksdale, 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. 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 turns east briefly at Lincoln Place, before continuing northeastward past Sycamore Street. The route travels along the edge of the city, and it soon intersects the western terminus of MS 6, which leads to US 278. The road enters Lyon north of the intersection, and it intersects Bobo and Fontaine Streets. MS 161 leaves the town north of Hopson Street and Roberson Road, and the road ends at a three-way junction with US 49 and US 61. US 61 was rerouted onto the new bypass around Clarksdale in August 2004, and MS 161 was designated on its old alignment. ;Major intersections
Walls
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. At Sullivan Road, the route enters the center of the town and begins to turn northward. MS 161 passes through the town, intersecting Second Street and Delta View Road. Past the center of the town, the road travels through more farmland and intersects MS 302 at a T-intersection. The route leaves the city limits of Walls, and it continues for before ending at US 61. In 1999, US 61 was rerouted out of Walls, and the old alignment became MS 161. ;Major intersections
