Blaine, leader of the "Half-Breed" Republicans, who were against corrupt patronage practices, was widely considered the logical Republican choice for President in 1876. Shortly before the party convention, however, a Democratic House investigating committee charged him with using his influence as speaker to secure a land grant for a railroad in Arkansas and with selling the railroad's bonds at a liberal commission. Blaine privately secured possession of the famous "Mulligan letters," which had been named as proof, before they could be placed on record, and he never surrendered them. He read portions of them, out of chronological order, before the House in an attempt to defend himself, but the episode was an important factor in his defeat for the presidential nomination at the 1876 Republican convention. Blaine, as U.S. Senator (1876-81), loyally supported President Rutherford B. Hayes.

In 1880, Blaine was again a candidate for the presidential nomination, but the Conkling faction successfully prevented his nomination. The deadlock was broken by the choice of Blaine's friend, Garfield, with Chester A. Arthur, a Conkling man, nominated for Vice President. Blaine became Garfield's Secretary of State, but upon the President's assassination resigned. Retiring to private life, he wrote Twenty Years of Congress (2 vol., 1884-86).

He was finally nominated for President in 1884 and ran against the Democratic candidate Grover Cleveland. Allusions to the "Mulligan letters" and to Cleveland's admitted paternity of an illegitimate child enlivened the bitter campaign. However, reform Republicans (mugwumps) such as Carl Schurz preferred Cleveland's untainted public record to Blaine's private virtue. Their defection was made the more important when a tactless New York Presbyterian clergyman, the Rev. Samuel D. Buchard, spoke, in Blaine's presence, of the Democrats as "the party whose antecedents are rum, Romanism, and rebellion." Blaine's failure to disavow the remark offended the large Irish Catholic vote in New York; he lost that state by a scant thousand votes and thereby lost the election.

In 1888, Blaine unexpectedly declined to run for President, supporting Benjamin Harrison, who, upon becoming President, made him Secretary of State again. Three days before the Republican convention of 1892, Blaine resigned to seek the nomination for President, but Harrison was renominated. Thereafter Blaine's health failed rapidly, and he died the next year.

As Secretary of State, Blaine was particularly energetic in fostering closer relations with the Latin American nations. During his second term in office he was able to bring about and preside over the first Pan-American Congress (see Pan-Americanism), thus laying the foundation for subsequent meetings, and the Pan-American Union was established. Blaine hoped to increase commercial relations among American nations by reciprocal tariff treaties, and although the McKinley Tariff Act prevented this, his idea of tariff "reciprocity" gained some credence. He also concluded a treaty with Great Britain to submit the fur-seal controversy to arbitration (see under Bering Sea).