When South Dakota was admitted as a state, Pettigrew was elected as South Dakota's first Senator to the United States Senate. He served from November 2, 1889 to March 3, 1901. He introduced a bill to fund the structure, recommending that native Sioux quartzite be used for construction of the state's first Federal building. He was re-elected in 1894, but left the Republican Party on June 17, 1896 to join the Silver Republicans, a faction of the Republican Party that opposed the party's position in support of the monetary gold standard. He was an unsuccessful candidate for reelection in 1900.