The resignation comes nearly two years after the 52-year-old Ensign said he had an extramarital affair with a former staffer, an acknowledgement that has been surrounded by ethics allegations. Ensign insisted that he's done nothing wrong.
Senate Ethics Committee named a special counsel in February to look into the matter, after the Justice Department and the Federal Election Commission investigated and then dropped their cases.
Ensign insisted Thursday that he's done nothing wrong, and said the appointment shook him because he had hoped the probes would end with the Justice Department.
"I was hopeful that, with the closure of these investigations against me the wear and tear on my family and me would soon be over. This was not the case," he said.
"As is its right, the Senate Ethics Committee is continuing its investigation of issues into which it has been inquiring for the past year and a half. Indeed, the Committee even decided recently to devote more resources to its investigation by hiring an outside counsel even though the issues have been viewed and reviewed by so many others," he said.
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.
Ensign's resignation would be effective May 3. Republican Gov. Brian Sandoval would appoint someone to serve the remainder of the term, which expires at the end of 2012.
Several Republican Party officials said Thursday they hoped Sandoval would appoint U.S. Rep. Dean Heller to Ensign's seat. The officials spoke on condition of anonymity to discuss internal deliberations.
Choosing Heller or another Republican would give the party the advantage of incumbency in a highly competitive seat that could decide which party controls the Senate after next year's elections.
U.S. Rep. Shelley Berkley and wealthy businessman Byron Georgiou have said they are candidates for the Democratic nomination.
Ensign announced in June 2009 that he had an extramarital affair with Cynthia Hampton, a former member of his campaign staff, and that he had helped her husband, Doug Hampton, a member of his Senate staff, obtain lobbying work with two Nevada companies.
Doug Hampton has been indicted for illegally lobbying the senator's staff. Federal law prohibits a former senior Senate aide from lobbying the Senate for one year after terminating employment.
Democratic Sen. Barbara Boxer, who chairs the Senate Ethics Committee, and GOP Sen. Johnny Isakson, the committee's vice chairman, said they will complete their investigation in a timely fashion.
"Senator Ensign has made the appropriate decision," the senators said in a statement Thursday.
Ensign announced in March he would not pursue re-election in 2012 to protect his family from campaign attacks involving his role in Doug Hampton's lobbying career. He said last month that the Senate investigation hadn't influenced his decision.
"If I was concerned about that I would have resigned, because that would make the most sense because then it goes away," he said in March.
On Thursday, the government watchdog group that requested the Senate ethics investigation said Ensign should have resigned sooner.
"Sadly, it's not because he's seen the error of his ways, or even to 'spend more time with his family," Citizens for Responsibility and Ethics executive director Melanie Sloan said in a statement. "The truth no one is likely to admit is that Sen. Ensign is being pushed out to give the Republican party a leg up in the 2012 election."
Associated Press writers Sandra Chereb in Carson City and David Espo in Washington, D.C., contributed to this report.