Established around 1932 as a new primary spur of SC 64 to SC 36 (today US 601). By 1938, SC 641 was extended west on new routing to SC 33/SC 331 (today US 321), in Sycamore. In 1942, its alignment was straighten, leaving Rivers Bridge Road (S-5-31/S-15-37). By 1948, SC 641 was extended west to Allendale, replacing part of SC 73. In 1952, it was extended west again to the southern boundary of the Savannah River Plant, replacing part of SC 28; reaching its apex of over 44 miles (71 km) long. Between 1968-1970, SC 641 was truncated at US 301, its former route replaced by SC 125.