In 1954, US 278 was extended from Guin, Alabama, to Augusta, Georgia. The extension was routed along US 43 from Guin to Hamilton, Alabama, then over SR 74 to the Georgia state line. In Georgia, US 278 was routed over SR 6 to Atlanta and SR 12 to Augusta. A further extension from Augusta to Jacksonboro, South Carolina, in 1955 was denied by AASHO.
In 1989, US 278 was rerouted through Dallas, Georgia; the former route through town was redesignated US 278 Byp. AASHTO approved another relocation through Rockmart, Georgia, in 1990; the former route through town became US 278 Bus. A third relocation the following year in Cedartown, Georgia, was also approved.
Alabama rerouted a section of US 278 in Guin over a section of SR 118 in 1995. At the same time, South Carolina rerouted the highway in Ridgeland over US 17 and SC 88.
Mississippi and Arkansas extended US 278 westward in 1997 from US 45 in Nettleton, Mississippi, to US 71 in Wickes, Arkansas. The following year, the highway was relocated on Hilton Head Island, South Carolina; the former routing became US 278 Bus.