Parker was nominated as the Republican nominee for the Seventh Congressional District on September 13, 1870. Backed by the Radical faction of the Republican party, Parker resigned his judgeship and devoted his energy to the campaign.
The heated campaign ended with Parker's opponent withdrawing from the race two weeks prior to the election. Parker easily defeated the replacement candidate in the November 8, 1870 election.
The first session of the Forty-second Congress convened on Saturday, March 4, 1871, with Isaac C. Parker taking his seat as a freshman representative in the chamber. His congressional career was a balance of resolving constituent needs while sponsoring domestic legislation. Representative Parker assisted veterans of his district in securing pensions, and lobbied for the construction of a new federal building in Saint Joseph. He sponsored legislation that would have allowed women the right to vote and hold public office in United States territories. On several occasions Parker sponsored legislation that would have organized the Indian Territory under a formal territorial government.
Representative Parker handily won a second term in November 1872, one local paper saying of him, "Missouri had no more trusted or influential representative in ... Congress during the past two years..." In his second term, Parker gained national attention for speeches delivered in support of the Bureau of Indian Affairs. His second term saw his concentrating on Indian policy, and fair treatment of the Tribes residing in the Indian Territory.
By the fall of 1874, the political tide had shifted in Missouri, and as a Republican, Isaac Parker had no chance of reelection to Congress. Like many others, he sought a presidential appointment to public office.