Originally numbered as the B716 in 1922, It was upgraded to A-road status as the A754 in the mid 1920s, presumably due to its importance, as it bypassed Lanark. This number did not last long, however, as it was renumbered as an eastward extension of the A721 in 1934. It retains this number except in Carluke, where the High Street is now closed to through traffic. The route started on the A73 in Carluke and headed east, out of town and across the moors to meet the A70 just north of Carstairs.
An official document from 16/05/1934 details the following changes: The whole of this route to be renumbered as A721