Mr Blunt, 71, is the fourth highest ranking Republican member of the Senate.
He joins Republican senators Richard Shelby, Rob Portman, Richard Burr and Pat Toomey, who have also announced they will not seek re-election.
“After 14 General Election victories — three to county office, seven to the United States House of Representatives, and four statewide elections — I won’t be a candidate for re-election to the United States Senate next year,” Mr Blunt said.
Mr Blunt was elected in 2010. Prior to joining the Senate, he served in the House for 14 years, and as Missouri's secretary of state for eight.
The senator did not offer a reason for his retirement.
“In every job Missourians have allowed me to have, I’ve tried to do my best,” Mr Blunt said in his video. “In almost 12,000 votes in the Congress, I’m sure I wasn’t right every time, but you really make that decision based on the information you have at the time.”
Mr Blunt said he still had a lot of work to do before he left office.
“There is still a lot to do, and I look forward to every day this year and next year as I continue to work for you in the Senate," he said. “Another lesson I learned here: Finish strong. And I intend to.”
A pair of Democrats have announced they plan to run for Mr Blunt's seat.
Scott Sifton, a former state representative and state senator, and businessman Timothy Shepard, will compete in the state's Democratic primary to run for Mr Blunt's seat.
However, political analysts do not believe the seat will be flipped.