The highway was 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 straightened, 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 long. Between 1968 and 1970, SC 641 was truncated at
US 301, its former route replaced by
SC 125. ==Junction list==