Day one: Virginia City
Nevada exists because of the 1859 Comstock Lode, and Virginia City is where it happened. Start in Reno, drive 25 miles south to Virginia City (elevation 6,200 feet). Walk C Street: the Territorial Enterprise building where Mark Twain worked, the Fourth Ward School Museum ($10), and the Chollar Mine tour ($15) which goes 400 feet into an actual 1861 shaft. Lunch at the Delta Saloon or the Palace. Sleep at the Silverland Inn or the historic Gold Hill Hotel (1861, Nevada's oldest continuously operating hotel), one mile south.
Day two and three: Austin and Eureka
Drive US-50 east 175 miles to Austin, a former silver camp that peaked at 10,000 people in the 1860s and now has 200. Walk to Stokes Castle, a three-story granite tower built in 1897, and the Austin Cemetery. Sleep at the Cozy Mountain Motel. Day three continue 70 miles to Eureka, once the second-largest city in Nevada and now the best-preserved. Tour the Eureka Opera House (1880, still operating), the Sentinel Museum, and the Jackson House. Sleep at the Sundown Lodge or the Jackson House Hotel.
Day four: Ely and Tonopah
Drive 77 miles east from Eureka to Ely, and spend a half day at the Nevada Northern Railway Museum — this is the standout attraction on the whole route. The steam train excursions ($40) run on original 1906 track and locomotives. Then drive south on US-6 and US-95 (about 4 hours) to Tonopah, silver town of the 1900s. Sleep at the Mizpah Hotel, restored 1907 property where Wyatt Earp tended bar. Do the Tonopah Historic Mining Park in the morning before flying out of Reno or driving back to Vegas (3.5 hours south).
Good to know
Are the mine tours actually underground?+
The Chollar Mine in Virginia City and the Nevada Northern Railway mine tour in Ely both go underground. Most other sites are surface museums or preserved headframes. If descending shafts matters to you, prioritize those two.
Can I do this route in reverse from Las Vegas?+
Yes and it's arguably better — start at Tonopah (3.5 hours from Vegas), work your way north through Ely, Eureka, Austin, and end at Virginia City with a flight out of Reno. You avoid backtracking and finish at the biggest, most restored town.