The Forest Reserve Act of 1891 allowed President Harrison to establish 13 million acres of previously unprotected land as forest reserves.

The first international crisis Harrison faced arose from disputed fishing rights on the Alaskan coast. Canada claimed fishing and sealing rights around many of the Aleutian Islands, in violation of U.S. law. As a result, the United States Navy seized several Canadian ships.

On December 28, 1890, a detachment of the U.S. 7th Cavalry Regiment commanded by Major Samuel M. Whitside intercepted a nonviolent band of Lakota people who had left the reservation fearful of being caught up in Indian hostilities. Whitside escorted the Lakota 5 miles westward to Wounded Knee Creek, where they made camp. The remainder of the 7th Cavalry Regiment, led by Colonel James W. Forsyth, arrived and surrounded the encampment. On the morning of December 29, U.S. Cavalry troops entered the camp to disarm the Lakota. After most of the Lakota warriors had already been stripped of their guns, soldiers began firing on the camp. By the time the massacre was over, more than 250 men, women, and children of the Lakota had been killed. The dead Lakota were buried in a mass grave, and twenty soldiers were awarded the Medal of Honor. In 2001, the National Congress of American Indians passed two resolutions condemning the military awards and calling on the U.S. government to rescind them.

Over the four years of Harrison's term in office, six new states were admitted to the Union, more than any previous administration: North Dakota and South Dakota (November 2, 1889), Montana (November 8, 1889), Washington (November 11, 1889), Idaho (July 3, 1890), and Wyoming (July 10, 1890).

In 1889, Harrison had a 36-second speech recorded on a wax phonograph cylinder, making him the first president in history whose voice was preserved for posterity.

The Democrats renominated former President Grover Cleveland, making the 1892 election a rematch of the one four years earlier. Cleveland ultimately won the election by 277 electoral votes to Harrison's 145, giving Harrison the distinction of being the only president whose predecessor and successor were the same man.

In 1896, Harrison at age 62 married Mary Scott Lord Dimmick, the widowed 37-year-old niece and former secretary of his deceased wife. Harrison's two adult children disapproved of the marriage and did not attend the wedding.

Harrison was diagnosed with the flu (then referred to as grippe) in February 1901. He was treated with steam vapor inhalation and oxygen, but his condition worsened. He developed pneumonia and died at his home in Indianapolis on March 13, 1901, at the age of 67.