He won re-election by a narrow margin, defeating Republican nominee Charles Evans Hughes. Wilson's re-election made him the first Democrat since Andrew Jackson to win two consecutive terms.

The Zimmermann Telegram was a secret diplomatic communication issued from the German Foreign Office in January 1917 that proposed a military alliance between Germany and Mexico against the United States. The telegram was intercepted and decoded by British intelligence. Revelation of the contents enraged Americans. On April 6, 1917, after Wilson asked Congress for "a war to end all wars" and "make the world safe for democracy," Congress voted to declare war on Germany.

Wilson's Fourteen Points took many domestic progressive ideas and translated them into foreign policy (free trade, open agreements, democracy and self-determination).

Wilson advocated for the establishment of a worldwide intergovernmental organization whose principal mission was to maintain world peace. The resulting League of Nations was incorporated into the Treaty of Versailles and other treaties with the defeated Central Powers, but Wilson was subsequently unable to convince the U.S. Senate to ratify that treaty or allow the United States to join the League.

While Wilson would prove himself less than progressive in other civil rights matters, he did manage to get one thing right. In a 1918 speech before Congress, he endorsed the women's suffrage movement: "We have made partners of the women in this war.... Shall we admit them only to a partnership of suffering and sacrifice and toil and not to a partnership of privilege and right?" That same year, the House passed a constitutional amendment providing for women's suffrage nationwide, but the amendment stalled in the Senate. Wilson continued to apply pressure, and the Senate finally approved the Nineteenth Amendment, which was ratified in August 1920.

On October 2, 1919, Wilson suffered a serious stroke, leaving him paralyzed on his left side, and with only partial vision in the right eye. He was confined to bed for weeks and sequestered from everyone except his wife and his physician. The First Lady determined what documents the president read and who was allowed to communicate with him. For her influence in the administration, some have described Edith Wilson as "the first female President of the United States."

In 1918, with World War I raging, Wilson wanted to be a model for Americans in supporting troops. Allowing his flock of sheep to roam the grounds and eat grass cut down on the manpower needed to maintain the lawn, an example of rationing manpower. The sheep's wool was auctioned off and raised $52,823 for Red Cross relief efforts.

Wilson vetoed a total of 44 bills (33 regular vetoes and 11 pocket vetoes), six of which were overridden by Congress.

The first meeting between an incumbent President of the United States and the reigning Pope occurred during President Wilson's participation in the Paris Peace Conference on January 4, 1919, when he met with Pope Benedict XV. It was also the first visit by a sitting U.S. President to Europe.

On February 2, 1924, after word went out that Wilson was dying, large numbers of admirers knelt in the snow outside his house to pray for him. They did not know that he had already uttered his last words: "I am a broken piece of machinery. When the machinery is broken ... I am ready."