The county was founded in 1890.  Blaine County was named after James Gillespie Blaine, a Representative and a Senator from Maine; born in West Brownsville, Washington County, Pa., January 31, 1830; graduated from Washington College, Washington, Pa., in 1847; taught at the Western Military Institute, Blue Lick Springs, Ky.; returned to Pennsylvania; studied law; taught at the Pennsylvania Institution for the Blind in Philadelphia 1852-1854; moved in 1854 to Maine, where he edited the Portland Advertiser and the Kennebec Journal; member, State house of representatives 1859-1862, serving the last two years as speaker; 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; Speaker of the House of Representatives (Forty-first through Forty-third Congresses); chairman, Committee on Rules (Forty-third through Forty-fifth Congresses); unsuccessful candidate for nomination for President on the Republican ticket in 1876 and 1880; appointed and subsequently elected as a Republican to the United States Senate to fill the vacancy caused by the resignation of Lot M. Morrill; reelected and served from July 10, 1876, to March 5, 1881, when he resigned to become Secretary of State; chairman, Committee on Civil Service and Retrenchment (Forty-fifth Congress), Committee on Rules (Forty-fifth Congress); Secretary of State in the Cabinets of Presidents James Garfield and Chester Arthur, from March 5 to December 12, 1881; unsuccessful Republican candidate for President of the United States in 1884; Secretary of State in the Cabinet of President Benjamin Harrison 1889-1892, when he resigned; aided in organizing and was the first president of the Pan American Congress; died in Washington, D.C., January 27, 1893; interment in Oak Hill Cemetery; reinterment at the request of the State of Maine in the Blaine Memorial Park, Augusta, Maine, in June 1920.

Blaine County is the birthplace of voice actor Clarence Nash, the voice of Donald Duck.  Prominent Oklahomans who have lived in Blaine County include authors William Cunningham, Earnest Hoberecht, Sidney Stewart, Fleta Campbell Springer, and Maud Richmond Calvert. Thompson B. Ferguson served as territorial governor. His wife, Elva Ferguson, was significant in her own right as journalist and editor of the Watonga Republican newspaper. Dr. Earl D. McBride, prominent bone specialist and founder of the McBride Clinic and Bone and Joint Hospital in Oklahoma City, once resided in Watonga.