Earlier this year, Reid suffered a serious eye injury while exercising at home, causing him to reconsider whether he would seek re-election in 2016.
"This accident has caused [my wife] Landra and me to have a little down time. I have had time to ponder and to think," Reid said. "We've got to be more concerned about the country, the Senate, the state of Nevada than about ourselves. And as a result of that, I'm not going to run for re-election."
Reid has led Senate Democrats for the past eight years, first as Senate majority leader from 2007 until this year, when Republicans took control of the Senate, bumping him to Senate minority leader.
Reid's departure will open up a battle for the top Democratic spot in the Senate as well as for his Nevada seat back home. Hours after announcing he would retire from the Senate, Reid threw his support behind Sen. Chuck Schumer, D-New York, to be the next Democratic leader.
"It's the caucus' decision but Senator Reid thinks Senator Schumer has earned it," Adam Jentleson, spokesman for Reid, said.
Prior to joining the Senate in 1987, Reid, a Mormon, served two terms in the House of Representatives and as Nevada's lieutenant governor for four years.