In 2010, John was elected to serve a second term in the Senate in a rare unopposed race. He was only the third Republican and the only South Dakotan to run unopposed for the Senate since direct elections were created in 1913. John was elected to a third term in 2016.

For the 117th Congress, John serves on the Agriculture, Nutrition, and Forestry Committee; the Commerce, Science, and Transportation Committee; and the Finance Committee. He serves as ranking member of the Commerce Committee’s Subcommittee on Communications, Media, and Broadband and ranking member of the Finance Committee's Subcommittee on Taxation and IRS Oversight. He also serves as the Senate Republican whip, the number two position in Senate Republican leadership, and has previously served as chairman of the Senate Republican Policy Committee from 2009–2011 and chairman of the Senate Republican Conference from 2012-2018.