Founded in 1901 at Richmond's Second Baptist Church, the league raised money and organized a network of Protestant voters through church visitations and sophisticated publicity. It aimed to close saloons and dismantle the liquor industry, which it blamed for a host of social and moral problems, wherever possible by means of restrictive licensing, local option referenda, state legislation, and ultimately outright prohibition of alcohol manufacture and sales. The league emphasized practical politics. Its dominant figure, the talented but severe Methodist cleric (later bishop) and educator from Blackstone, James Cannon Jr., rejected third-party tactics and instead worked with officeholders and politicians who actually held power, many of whom opposed prohibition.

The Virginia league quickly established itself as a political force. After its initial superintendent, an outsider appointed by the national league, was assaulted by a judge he had criticized, league publicity helped bring about the impeachment and removal from office of the offending magistrate. Cannon was named to the league's powerful Executive Committee in 1903, became president in 1904, and assumed day-to-day operations as superintendent in 1909. He immediately attacked the liquor industry at its weakest points. Collaborating with prominent legislators, Cannon drafted legislation in 1903 and 1908 that closed the notoriously unruly rural saloons. The league directed local option elections that by 1909 had banned saloons from eighty-six out of one hundred counties.

Yet Virginia's largest cities remained defiantly wet, and the conservative organization of U.S. senator Thomas Staples Martin, which controlled the state Democratic Party, was unfriendly to prohibition. In other southern states, the Anti-Saloon League was identified with the progressive wing of the Democratic Party, but the Virginia league fashioned an alliance with Martin in 1909. The organization backed a dry candidate for governor, and, in turn, the league withheld calls for state prohibition and endorsed organization candidates. By 1912 the league had demanded passage of an enabling act to allow a state prohibition referendum. Martin's wet organization blocked the bill until league threats to throw its support to the Virginia Progressive Democratic League resulted in passage of the enabling act in 1914.

That September Virginians endorsed state prohibition, which went into effect in 1916. The league helped draft the prohibition statute, which barred the manufacture and sale of intoxicating beverages, but allowed a personal use exemption. Another league-sponsored bill created a state prohibition commissioner. Although wets and some dry legislators offended by Cannon's lobbying and cooperation with the Martin machine denounced the league's members as "ecclesiastical politicians," the league remained powerful until the end of national prohibition in 1933.