McKinley won the election by a fairly comfortable margin, taking 51 percent of the popular vote and 271 electoral votes. Democrats remained loyal to their champion after his defeat; many letters urged him to run again in the 1900 presidential election. William's younger brother, Charles W. Bryan, created a card file of supporters to whom the Bryans would send regular mailings to for the next thirty years. The Populist Party fractured after the election; many Populists, including James Weaver, followed Bryan into the Democratic Party, while others followed Eugene V. Debs into the Socialist Party.
Because of better economic conditions for farmers and the effects of the Klondike Gold Rush, free silver lost its potency as an electoral issue in the years following 1896. In 1900, President McKinley signed the Gold Standard Act, which put the United States on the gold standard. Bryan remained popular in the Democratic Party and his supporters took control of party organizations throughout the country, but he initially resisted shifting his political focus from free silver. Foreign policy emerged as an important issue due to the ongoing Cuban War of Independence against Spain, as many Americans supported Cuban independence. After the explosion of the USS Maine in Havana Harbor, the United States declared war on Spain in April 1898, beginning the Spanish–American War. Though wary of militarism, Bryan had long favored Cuban independence and he supported the war. He argued that "universal peace cannot come until justice is enthroned throughout the world. Until the right has triumphed in every land and love reigns in every heart, government must, as a last resort, appeal to force".
The 1900 Democratic National Convention met in Kansas City, Missouri, the westernmost location that either major party had ever held a national convention. Some Democratic leaders opposed to Bryan had hoped to nominate Admiral George Dewey for president, but Bryan faced no significant opposition by the time of the convention and he won his party's nomination unanimously. Bryan did not attend the convention, but he exercised control of the convention's proceedings via telegraph. Bryan faced a decision regarding what issue his campaign would focus on. Many of his most fervent supporters wanted Bryan to continue his crusade for free silver, while Democrats from the Northeast advised Bryan to center his campaign on the growing power of trusts. Bryan, however, decided that his campaign would focus on anti-imperialism, partly to unite the factions of the party and win over some Republicans. The party platform contained planks supporting free silver and opposing the power of trusts, but imperialism was labeled as the "paramount issue" of the campaign. The party nominated former Vice President Adlai Stevenson to serve as Bryan's running mate.
Bryan's defeat in 1900 cost him his status as the clear leader of the Democratic Party and conservatives like David B. Hill and Arthur Pue Gorman moved to re-establish their control over the party and return it to the policies of the Cleveland era. Meanwhile, Roosevelt succeeded McKinley as president after the latter was assassinated in September 1901. Roosevelt prosecuted antitrust cases and implemented other progressive policies, but Bryan argued that Roosevelt did not fully embrace progressive causes. Bryan called for a package of reforms, including a federal income tax, pure food and drug laws, a ban on corporate financing of campaigns, a constitutional amendment providing for the direct election of senators, local ownership of utilities and the state adoption of the initiative and the referendum. He also criticized Roosevelt's foreign policy and attacked Roosevelt's decision to invite Booker T. Washington to dine at the White House.
It has been suggested by some economists, historians, and literary critics that L. Frank Baum satirized Bryan as the Cowardly Lion in The Wonderful Wizard of Oz, published in 1900. These assertions are based partly on Baum's history as a Republican supporter who advocated in his role as a journalist on behalf of William McKinley and his policies.