In 1856 he helped organize the Republican party in Iowa. At the convention in Iowa City, Grinnell was instrumental in "the delicate task" of bringing together abolitionists, temperance advocates, Know Nothings, and former Whigs. He won election to the state senate in 1856 and 1858 on the platform of temperance, free public education for all, and free soil. He tirelessly argued that not only were such positions morally correct, but they would bring prosperity by increasing the value of labor and the land. Despite securing a public school law, the creation of an agricultural college at Ames, and a temperance law, he was not renominated for a third term. His reputation might have been injured in February 1859, when he entertained and assisted John Brown and several fugitive slaves. Grinnell was a delegate to the 1860 Republican National Convention and became a devoted supporter of Abraham Lincoln. From 1861 to 1863 Grinnell was a special agent of the Post Office Department, giving him ample opportunity "to fan the fires of patriotism" and encourage army enlistments (Grinnell, p. 124).
With some difficulty, Grinnell was nominated for Congress from Iowa's Fifth District in 1862 and, thanks to a substantial soldiers' vote, won the election. He was reelected by a more comfortable margin in 1864. Grinnell could be counted among the Radical Republicans in favor of a vigorous prosecution of the war, the enlistment of blacks, and Radical Reconstruction measures. Years later he regretted not punishing the South further by insisting on "a territorial probation before admission" (Grinnell, p. 158).