MS 145 begins in Lee County in the eastern part of Shannon at an interchange between US 45, US 45 Alternate, and US 278. It heads northwest as a two-lane highway to bypass downtown along Noah Curtis Street before turning north along Romie Hill Avenue at an intersection with MS 245. The highway leaves Shannon and crosses over a creek to enter Verona along Raymond Avenue. MS 145 widens to a four-lane undivided highway as it passes through industrial areas before passing through downtown. It passes through neighborhoods before crossing into Tupelo at an intersection with US 278/MS 6 (Pontotoc Parkway). The highway heads north through a business district (along Gloster Street), where it has an intersection with S Green Street (unsigned MS 769), before crossing over a creek and becoming concurrent with MS 178 (Main Street), bypassing downtown to the west as they passes through neighborhoods. They then have an interchange with McCullough Boulevard, where MS 178 splits off, and MS 145 continues north to have another intersection with Green Street (MS 769) before leaving Tupelo, crossing a creek and passing under I-22/US 78. MS 145 narrows to two-lanes and has an interchange with the Natchez Trace Parkway before entering Saltillo and passing a business district before having an interchange with US 45. It bypasses downtown to the northwest, having intersections with MS 363 (Mobile Street) and MS 766 (N 3rd Street) as it passes through neighborhoods, before leaving Saltillo and passing through rural areas. It passes through Guntown, where it has an intersection with MS 348, before passing through Baldwyn, where it has a concurrency with MS 370 and crosses into Prentiss County.