It runs for 118.3 miles (190.4 km), serving the counties of Lauderdale, Newton, Neshoba, Winston, Attala, and Holmes.

It heads northwest as a two-lane highway through wooded and hilly terrain for several miles, where it passes through the community of Whynot and has an intersection with MS 496, before widening to a four-lane divided highway as it enters the Meridian city limits.

The highway now enters the Philadelphia city limits along Holland Avenue and immediately passes through a business district before passing through neighborhoods to become concurrent with MS 16, with the road heading west into downtown as a one-way pair between Main Street and Beacon Street.

MS 19 now leaves Philadelphia and travels through another portion of the Mississippi Band of Choctaw Indians Reservation, where it passes through the community of Choctaw and crosses the Pearl River, before curving to the northwest to have an intersection with MS 395 in Arlington and enter some hilly terrain as it briefly crosses into the southwestern-most corner of Winston County, where it has an interchange with MS 25.

MS 19 passes through neighborhoods before leaving Kosciusko and traveling mostly wooded areas for the next several miles, where it passes through the community of Possumneck and has an intersection with MS 440, before crossing the Big Black River into Holmes County.