The highway continues over bumpy land through or near the towns of Hayti, Portageville, and New Madrid before reaching an interchange with US 60 and I-57 just south of Sikeston.

The next interchange, US 62, provides access into the city of Sikeston and one of its most popular attractions, Lambert's Cafe, the "Home of the Throwed Rolls".

Exit 95, Route 74 east, provides direct access to the Bill Emerson Memorial Bridge into southern Illinois.

In the last few miles of I-55 in the state of Missouri, there is an interchange and brief overlap with I-44 before reaching the Poplar Street Bridge crossing into Illinois.

The white supremacy group Ku Klux Klan began fighting several court battles with the state of Missouri after the state disputed its right to sponsor a stretch of freeway in Saint Louis County and Jefferson County, near St. Louis.