The Republican says ongoing ethics probes are putting too much strain on his family.
Ensign has faced allegations of ethics violations since admitting two years ago that he had an affair with a former staffer and helped her husband get lobbying work.
The Justice Department and Federal Election Commission dropped their cases, but the Senate Ethics Committee recently named its own special counsel to examine the issue.
In his statement , Ensign said that he could no longer put up with the intense focus of the affair and the ethical issues.
"While I stand behind my firm belief that I have not violated any law, rule, or standard of conduct of the Senate, and I have fought to prove this publicly, I will not continue to subject my family, my constituents, or the Senate to any further rounds of investigation, depositions, drawn out proceedings, or especially public hearings," he said.
Republican Gov. Brian Sandoval would appoint someone to serve the remainder of Ensign's term, which expires at the end of 2012.
The Associated Press contributed to this report.