After passing through the city, the route continues on a winding path until it reaches Guin, where it turns north and gains US 43.

It continues onward and enters the William B. Bankhead National Forest, where Double Springs lies.

It then exits the National Forest and enters Addison, which is home to its junction with CR 41, which is a corridor connecting Jasper, Arley, Danville, and Decatur.

It continues east and eventually enters Holly Pond, which is home to its junction with SR 91.

The route has no more major junctions at this point as it crosses through Cherokee County.

It passes through highly hilly terrain and crosses into Cleburne County.

From its creation until at least 1985, the route followed present-day Winston County Roads 3800 and 3700, crossing Brushy Creek at a now-abandoned bridge before climbing up to join its present-day route into Addison.

[5] During the 1960s–1980s, there were some different variations of the routing of US 278 through the cities of Gadsden and Attalla, however construction of four-lane segments on the western side of Gadsden and in Attalla allowed the highway to be placed on its current route which has been in place since the mid-1980s.

began where the four-lane segment began on the northeast side of Piedmont, then traveled southwest into the center of the city and intersected SR 9 and then traveled to the north, concurrent with SR 9 until it intersected the four-lane US 278 on the northern edge of the city.

A four-laning project is ongoing east of Gadsden near the town of Hokes Bluff.

It is signed however along a separate 4.9-mile-long (7.9 km) east-west segment in Marion County.