Current US 21/221 from NC to Independence except at the New River it used Grandview Ln and Old River Ln (SR 700/701).
East of Independence, US 221 followed followed US 58-221 east to VA 274, then VA 94 south to SR 882 to Galax as Greenville Rd, then W. Stuart Dr (makes a 90 degree turn at MacArthur) back to US 58-221 to Glendale Rd out of Galax and on SR 887 out to near Woodlawn before using SR 872 Woodlawn Rd and again US 58-221 to Hillsville.
From Hillsville, US 221 followed pretty much its current routing to central Roanoke except SR 734 at Copper Hill; SR 711 at Bent Mountain; Old Cave Spring Rd.

VA 205 Hillsville to Roanoke 1929 Official

most of US 221's original routing 1933 Conoco

Adjustments: During 1932, Virginia intended to extend US 221 all the way to Reedville by replacing VA 10 from Roanoke to Lynchburg; US 60 from Lynchburg to Richmond; VA 13 Richmond to Callao; VA 607 Callao to Reedville.
By May 1933 (AASHO), the US 221 extension was shelved in favor of US 86 from Roanoke to Burkeville and US 33 from Burkeville to Reedville. In the end these became US 460 and US 360 respectively.

most of US 221's planned extension to Reedville
1933 draft route list

US 221 ending at Elm/Jefferson 1933 Official

US 221 ending at Franklin/Jefferson 1934 Official

US 221 on split routing 1975 VDOT City Atlas

In March 1956 (CTB), US 221 was removed from SR 872 Woodlawn.
In Aug 1958 (CTB), US 221 was removed from SR 887 Glendale Rd east of Galax.
In Feb 1966 (CTB), I think US 221 was removed from Old Cave Spring Rd when VA 419 was totally rebuilt through there.
In Jan 1970 (CTB), US 221 was removed from W. Stuart Drive in Galax.
In Dec 1970 (CTB), US 221 was extended north by following US 220 Bus and US 11, then US 460 east to Bedford, then replacing US 460 to US 221's current endpoint. Note that a month earlier AASHO denied a request to renumber former US 460 from Bedford to Lynchburg as US 460 ALT.

US 460 Bedford to Lynchburg 1970 Official

US 221 extended to Lynchburg 1972 Official

In Dec 1974 (CTB), US 221 was removed from SR 734 in Copper Hill.
In Nov 1979 (CTB), US 221 was placed on its current route between Independence and VA 94 (replacing VA 212), leaving behind VA 274 and an extended VA 94.

US 58-221 original route 1978 Official

VA 212 replaced by US 58-221. 1980 Official

In 1981, US 221 (with US 460 Bus and US 501 Bus) was removed from a one-way split between 12th St and US 29 Lynchburg Expressway. NB traffic had been using Buchanan and either 14th or 15th St.

US 221 on split routing in Lynchburg 1977 Official

Split routing removed 1989 Official

In Oct 1990 (CTB), US 21 was rebuilt from the NC Line across the New River, leaving behind parts of SR 700 and 701.
In June 1997 (CTB), US 221 was removed from SR 840 Pilgrim Rd and SR 643/841 Brookhill Rd in the Goode area in Bedford County.
About 1999, US 221 was posted to use the US 460 and VA 122 bypasses of Bedford, leaving behind US 221 Business.
The 2020 Traffic log still shows the split alignment in Roanoke. However, it has not been posted in the field back to at least the early 1990s.
Improvements:  Upon designation in 1931, US 221 was fully paved from the North Carolina line to Hillsville and about 8 miles from Roanoke south.
In 1933, US 221 was paved south to Bent Mountain.
In 1934, US 221 was paved south to Copper Hill.
In 1937, US 221 was paved south to Floyd.
In 1938, US 221 was paved from Hillsville to the Floyd County line and from Willis to Floyd..
In 1939, the remainder of US 221 was paved.
The earliest multilaning of US 221 was in 1970, on its new US 460 concurrency from Roanoke to Bedford.
In 1975, US 221 was multilaned from current VA 94 to Galax
In 1978, US 221 was 4-laned from I-77 to Hillsville
In 1983 or 1984, US 221 was multilaned from I-77 west 2 miles
In 1985 or 1986, US 221 was multilaned from Galax to I-77; also in the Cave Spring area
In 1988, US 221 was multilaned from Cave Spring to the Roanoke city line; also on its US 11 duplex.
In 1993 or 1994, US 221 was multilaned from Graves Mill Rd Lynchburg west about 2 miles.
In 1995 or 1996, US 221 was multilaned from US 501 to Graves Mill Rd.
In 1997 or 1998, US 221 was mutlilaned from VA 274 to VA 94
In 1999, US 221 was multilaned on its US 460 duplex around Bedford.
In 2009 or 2010, US 221 was multilaned further west of Lynchburg to SR 663.
Posted:  Fully posted; last known cutouts are in Hillsville; Roanoke, Bedford, and Galax cutouts were removed in the early 1990s.
Multiplexes:  US 460 Bus, US 501 Bus (0.59 mi)
US 460 Bus (0.67 mi)
VA 122 (1.71 mi)
US 460 Bus, VA 122 (0.10 mi)
US 460, VA 122 (1.44 mi)
US 460 (22.50 mi)
US 460, VA 220 ALT (4.81 mi)
US 11, VA 116 (0.50 mi)
US 11, US 220 Bus, VA 116 (0.30 mi)
US 220 Bus, VA 116 (0.28 mi)
US 220 Bus (0.30 mi)
US 58 Bus (1.56 mi)
US 58 (26.81 mi)
US 21 (3.86 mi)
Legislative names:  Colonial Trail from Bedford to Lynchburg (3-24-30 designation predates US 221)
William D. Thompkins Memorial Bridge over Big Reed Island Creek (2-20-40); Veterans Memorial Bridge over New River (since 5/16/02); Taylor G Vaughan Memorial Bridge over Chestnut Creek in Galax (since 3/9/42); R.A. Doughton Memorial Bridge over the New River (2-18-38)
Other names:  Kemper St/12th St/Fort Ave/Oakley Ave/Lakeside Dr (Lynchburg); Forest Rd (Bedford Co e of Bedford); Independence Blvd/Main St (Bedford); W. Lynchburg-Salem Tpk (Bedford Co w of Bedford); Blue Ridge Blvd (Botetourt Co); Challenger Ave (Roanoke Co e of Roanoke); Orange Ave/Williamson Rd/Franklin Rd/Elm Ave/Brambleton Ave (City of Roanoke); Bent Mountain Rd (Roanoke Co s of Roanoke); Floyd Hwy (Floyd Co); Main St (Floyd); Floyd Pike (Carroll Co n of Hillsville); Stuart Dr (Hillsville); Carrollton Pike (Carroll Co w of Hillsville); Stuart Dr/Reserve Blvd (Galax); Grayson Pkwy (Grayson Co e of Independence); Main St (Independence); New River Pkwy (US 21 duplex)
Scenic Byway:  No segments
Comments: US 221 nationally has expanded to 5 states, but is never really a featured route anywhere. It is a poor-man's Blue Ridge Pkwy, which it crosses several times (twice in Virginia - Adney's Gap southwest of Roanoke (a brush encounter) and northeast of Roanoke with US 460, a full interchange).
I'm not sure extending US 221 to Lynchburg makes a lot of sense. An extension of VA 291 from Lynchburg to Bedford would've accomplished the same thing.
The 1962 Topo Map (discovered by NE2) shows US 221 north extended along 2nd St to end at US 11 ALT-460. I have found no other evidence this happened, although some Roanoke changes are not in the CTB Minutes. I-581 is built nearly on top of 2nd St. The changes in the 1955 and 1970 CTB clearly show US 221 ending at US 220 at the time of those actions, and several pictures I've seen from the 1950s-60s show US 221 ending there as well. Lastly, questions I have include why wasn't 2nd St made VA 116 if this needed to be in the primary system and why wasn't US 221 defined to end at the Orange/Williamson intersection once I-581 made 2nd St obsolete, if it was deemed important to have US 221 end at US 460?