Blaine taught at the Western Military Institute, Blue Lick Springs, Kentucky. He returned to Pennsylvania and studied law. From 1852-1854, he taught at the Pennsylvania Institution for the Blind in Philadelphia.
In 1854, Blaine moved to Maine, where he edited the Portland Advertiser and the Kennebec Journal. He served as a member in State House of Representatives from 1859-1862, serving the last two years as speaker.
Blaine was elected as a Republican to the Thirty-eighth and to the six succeeding Congresses and served from March 4, 1863, to July 10, 1876, when he resigned. He was Speaker of the House of Representatives (Forty-first through Forty-third Congresses). He served as chairman of the Committee on Rules (Forty-third through Forty-fifth Congresses).
Blaine was appointed and subsequently elected as a Republican to the United States Senate to fill the vacancy caused by the resignation of Lot M. Morrill. He was re-elected and served from July 10, 1876, to March 5, 1881, when he resigned to become Secretary of State. While in the Senate, he served as chairman of the Committee on Civil Service and Retrenchment (Forty-fifth Congress) and Committee on Rules (Forty-fifth Congress).
Blaine was Secretary of State in the Cabinets of Presidents James Garfield and Chester Arthur from March 5 to December 12, 1881. He was unsuccessful Republican candidate for President of the United States in 1884 (See U.S. presidential election, U.S. presidential election, 1884.) He subsequently served as Secretary of State in the Cabinet of President Benjamin Harrison from 1889-1892, when he resigned.
Blaine also aided in organizing and was the first president of the Pan American Congress.