By the 1890s, Allison had become one of the "big four" key Republicans who largely controlled the Senate, along with Orville H. Platt of Connecticut, John Coit Spooner of Wisconsin and Nelson W. Aldrich of Rhode Island.

He also helped pass the Hepburn Act by offering the Allison amendment, which granted courts the power to review the Interstate Commerce Commission's railroad rate-setting.

Allison sought a record seventh term in 1908, but died shortly after winning the Republican primary against progressive leader Albert B. Cummins.

While in Ohio, Allison's rise in politics coincided during a period of time where the Whig Party was facing collapse due to internal divisions over slavery.

Although the city was a stronghold for the Democratic Party at the time, Allison's ties with a law partnership and a Presbyterian church proved to successfully propel him into the state GOP leadership.

In the 1862 midterms, Allison ran for the U.S. House of Representatives from the third district which included Dubuque, challenging incumbent Republican congressman William Vandever.

[2] Benefiting from connections to Kirkwood in addition to railroad interests, he denied Vandever renomination and won the general election.

[5] In the House, Allison sided with the powerful Radical Republican wing of the party which frequently opposed President Lincoln's policies as being too moderate,[2] instead favoring a harsher treatment of the Confederacy.

After being re-elected in 1864,[6] he was a member of the powerful Ways and Means Committee, in addition to emerging as a leading expert on protective tariffs and railroads.

[7] The Radical Republicans were not unified on ideological issues aside from their advocacy of harsher Reconstruction policies to ensure and safeguard the constitutional rights of blacks.

[10] In the 1871 state legislative races, candidates were nominated and elected on the direct issue of whether they would vote for Harlan, Allison or James F. Wilson for senator.

[11] Enough legislators who favored Allison were nominated and elected in 1871 that in January 1872 he won the required number of votes to take Harlan's U.S. Senate seat, effective March 4, 1873.

He chaired the 1884–1886 Allison Commission, a bipartisan joint congressional committee "among the first to explore the question of whether federal intervention politicizes scientific research.

[14] In 1885, the Commission's finding of misuse of funds at the United States Coast and Geodetic Survey led to the dismissal of several officials but exonerated Charles Sanders Peirce.

After 1897, he was chosen as chairman of the Republican caucus, an unofficial position, but one generally accorded to the most venerable and respected party member in the Senate.

Eminently conservative, trusted by the railroad interests, Allison's pragmatism made him the centrist that everybody could deal with, including Democratic colleagues.

Nobody thought that it could pass, but it put the best face on protectionist principles and later served as a model for the 1890 McKinley Tariff, which Allison played a large part in framing.

'...When he rises in his place in the Senate, he disdains to talk as if he were making a speech; he leaves all that to the youngsters, whose sum of knowledge does not equal all that he has forgotten.

[11] However, this time the incumbent prevailed; Allison won a clear victory over Cummins by over ten thousand votes.

[21] As a reflection of the nature of its preference for Allison over Cummins, the Ames Times reported the primary results under a two-level banner headline simply stating "GLORY TO GOD!

There is an imposing memorial to Allison by sculptor Evelyn Beatrice Longman on the grounds of the Iowa State Capitol in Des Moines.