A second segment of 92.83 miles (149.40 km) runs from Highway 17 in Diaz east to the Mississippi River.

The route begins at Highway 17 in Diaz and runs east, before meeting I-57/US 67 in Newport.

Both routes briefly meets Highway 181 near Dell before turning northeast to Blytheville.

The route continues east to cross over I-55 (exit 67) in a frontage road interchange where US 78 departs from the highway to enter I-55.

[7] It was extended to the Mississippi River on April 24, 1963, as part of a major expansion of the state highway system.