"I just think it's time for me to step aside," Harkin told the AP.
Harkin, first elected in 1984, ranks seventh in seniority, and fourth among majority Democrats. He is chairman of the health, education, labor and pensions committee, and chairman of the largest appropriations subcommittee.
Harkin has long aligned with the Senate's more liberal members, and his signature legislative accomplishment is the 1990 Americans with Disabilities Act.
He also served as a key salesman of President Obama's 2010 health care bill to the wary left.
"I'm not saying that giving this up and walking away is easy. It's very tough," Harkin said at his rural Iowa home south of Des Moines. "But I'm not quitting today. I'm not passing the torch sitting down."
Harkin's news defied outward signals. Besides being beloved in his party, Harkin has $2.7 million in his campaign war chest, second most among members nearing the end of their terms, and was planning a gala fund-raiser in Washington next month featuring pop star Lady Gaga.
Although members of his family have been diagnosed with cancer, Harkin said his health is good - and reported a recent positive colonoscopy. But he said "you never know," and that he wanted to travel and spend his retirement with his wife Ruth "before it's too late."
He also nodded to his political longevity: "The effect of that cascades down and it opens a lot of doors of opportunity" for future candidates, he said.