In 1859, when the Comstock Lode made headlines, he was again attracted to mining. He established a small mill, called the Sutro Metallurgical Works, in East Dayton, Nevada, for the reduction of ores by an improved process of amalgamation, and was responsible for planning and construction of the Sutro Tunnel. This tunnel made it possible to drain and ventilate the many mines in the Comstock Lode and to permit the miners to safely bring out the rich silver ore.

In 1879 Sutro sold his tunnel to the McCalmont brothers and countless lesser investors, and he returned to San Francisco.

He ran for mayor of San Francisco in 1894 on the Populist ticket, as the "Anti-Octopus" candidate, which opposed the politics of the Southern Pacific Railroad. He served one term.

At one time he owned one-twelfth of the acreage in San Francisco. He purchased the Cliff House in the early 1880s and a thousand acres of land facing the ocean, now named Sutro Heights. He also built the famed Sutro Baths and planted Sutro Forest. He owned the finest private library in the United States, most of which was destroyed during the Great Earthquake and Fire.

Adolph Sutro died in San Francisco August 8, 1898.