[citation needed] In 1939, SC 45 was rerouted onto new primary routing west of Eutawville to its current northern terminus with US 15/SC 31 in Wells.

[citation needed] In 1942, both Santee Reservoir (Lake Marion) and Pinopolis Reservoir (Lake Moultrie) begin to be filled causing SC 45 to be altered.

SC 45 was rerouted southeast along SC 6 to Cross then north around Lake Moultrie to meet back with the original SC 45 east of Eadytown; the old alignment became secondary roads Fredcon Road (S-38-137) and Edgewater Road (S-8-31) with the rest under Lake Marion.

In 1950, SC 45 was rerouted west of Cross onto new primary routing and bridge over the Diversion Canal; the old alignment that hugged Lake Moultrie's shoreline became secondary road Ranger Drive (S-8-132).

Around 1952, SC 45 was taken off a 4-mile (6.4 km) concurrency with US 52 and given a new routing between Pineville and St. Stephen; this left behind Colonel Manham Drive (S-8-6).