In January 2014, Lankford announced he would run in the 2014 Senate special election to succeed retiring Republican Senator Tom Coburn. Lankford won the June 2014 Republican primary, defeating former state House speaker T.W. Shannon and former state senator Randy Brogdon. In November, Lankford won the election for the final two years of Coburn's second term, defeating retiring state senator Constance N. Johnson by a margin of 557,002, 67.9%, to Johnson's 237,923, 29.0%, with independent candidate Mark Beard collecting 25,965 votes, 3.2% of the total.
Lankford was elected to a full six-year term in the Senate at the 2016 Oklahoma United States Senate election, defeating Democratic consultant Mike Workman with 67.7 percent of the vote. As in 2014, he won in a landslide, carrying every county in the state.
In 2014 Lankford was endorsed by the National Rifle Association and had an "A" rating for his consistent support of pro-gun legislation. Lankford supports loosening restrictions on interstate gun purchases. He opposes firearm microstamping, a controversial method of imprinting casings with a unique marking to match it with a specific firearm, and would allow veterans to register unlicensed firearms.