"Words are inadequate to fully express our appreciation for the friendship and support you have given to us over the past three decades," Johanns, 62, and his wife, Stephanie, wrote in an e-mail to supporters.
"At the end of this term, we will have been in public service over 32 years," he said. "Between the two of us, we have been on the ballot for primary and general elections 16 times and we have served in eight offices. It is time to close this chapter of our lives."
The departure of Johanns, a former governor, was not expected, The Washington Post said. Republicans are expected to win the open seat in the red state.
Johanns was one of four Republicans to vote to bring the nomination of former Sen. Chuck Hagel, R-Neb., as defense secretary to a vote.
Looking ahead, Johanns and his wife said in their email, "We want a quieter time with our focus on each other, our family and our faith."