The current US 421 Business was the 1st one created, in Nov 1969 (NCDOT) as an addition to NC 115 and a renumbering of part of US 421-A through N. Wilkesboro.
As best I can tell, US 421 Business has always used Main-6th-D both direction through North Wilkesboro.

NC 115 and US 421-A through N. Wilkesboro 1962 Wilkes County

US 421 Business appears 1972 Wilkes County

The 3rd US 421 Business was created Feb 2015 when a newly constructed bypass of Sanford was built around the east and north of town.

Now a look at the decommissioned US 421 Business route:
The 2nd US 421 Business was created Aug 1971 (NCDOT) as an addition to US 117-NC 133 across the NE Cape Fear River and an upgrade to SR 1627 down 3rd St to 16th St where it connected back up with US 421. This had been mainline US 421 up until Sept 1969 (NCDOT).
In 1975, US 421 Business was decommissioned, leaving behind US 117-NC 133 across the river and US 17 Business (since moved) on 3rd St south of Market St.

3rd St unnumbered 1971 Official

US 421 Business appears 1972-73 Official

US 421 Business disappears 1975 Official