In February 1861, Harris was elected a U.S. Senator from New York to succeed William H. Seward who did not seek re-election, but would be appointed U.S. Secretary of State by Abraham Lincoln. In the U.S. Senate, Harris served on the Committees on Foreign Relations, the Judiciary, and the Select Joint Committee on the Southern States. Although he supported the administration in the main, he did not fear to express his opposition to all measures, however popular at the time, that did not appear to him either wise or just. He visited Lincoln at the White House often and grew a friendship with him. He was also a good friend of his predecessor in the Senate, William H. Seward.