In Kenedy, SH 72 intersects  US 181 and passes through the city's downtown along Main Street; SH 72's only business route is also in this city. To the east of the city, SH 72 intersects  SH 239 and passes through Runge before entering DeWitt County.
The highway passes through Yorktown along that city's Main Street, intersecting  SH 119. SH 72 intersects  US 87 to the west of Cuero before it turns to the east and into the city.