Lieutenant Governor Timothy P. Murray will resign from the administration next month to run the Worcester Chamber of Commerce, positioning himself as a hometown cheerleader far from Beacon Hill where he saw his reputation tarnished the last few years.

In a dramatic exit from the State House, Murray, once widely considered a front-runner for the governorship next year, will serve as president and CEO of the Worcester Regional Chamber of Commerce. He becomes the first lieutenant governor to resign midterm since John F. Kerry joined the US Senate in 1985, leaving the state’s second-highest governmental position open until a new administration takes office in early 2015.

Murray has wielded a broader portfolio than many of his predecessors. But controversies over his ties to disgraced local official and an extraordinary early-morning car accident have hobbled him politically since late 2011.

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“I have mixed feelings about it,” Murray said in an interview with the Globe Wednesday. “When I think about this job and its potential and the vision of where they want to take it, I get very excited.”

He dismissed the notion that his ties to former Chelsea Housing Authority chief Michael McLaughlin, who raised money for Murray’s campaign and earlier this year pleaded guilty to federal felony charges of concealing his salary, or his November 2011 car accident fueled his decision. As a longtime advocate for the homeless, Murray said, McLaughlin’s criminal behavior “pisses me off.”

“This has nothing to do with that,” Murray said during an interview in his office. “This is nothing that I sought out. People came to me.”

His resignation will take effect June 2.

At a State House press conference on Wednesday, Murray said he initially dismissed the chamber’s offer, but grew more enthusiastic when officials there talked to him about their plans to enhance the group’s performance. His political woes, he said, were not a factor.

“People are going to believe what they want to believe, but to me this is a right fit and a right decision, and I struggled with the idea of leaving early, because there are still items on the punchlist,” Murray said.

Two Patrick administration officials said Murray, who now makes less than $125,000 a year, is expected to earn over $200,000 as head of the Worcester chamber.

Murray also voiced the frustrations common among many in the state outside the metro Boston region: that much of the political and commercial focus is on the capital.

“It’s often times very Boston-centric, and that’s at the expense of other regions,” Murray said. “The fact of the matter is, if you took central Massachusetts and plopped it down in any other state in the country, it would be seen as a major economic force, which it is. But we don’t promote it and sell it.”

Murray earlier this year announced he would not seek the corner office next year, despite years of anticipation that he would look to graduate from the number-two post. As lieutenant governor, Murray worked as Governor Deval Patrick’s liaison to local officials, taking the lead on veterans’ affairs, and homing in on transportation and economic development issues.

The administration was engaged in trying to help Murray land a job in the private sector, according to a person familiar with those efforts.

“His departure leaves a very big hole in our team. So, I’m happy for him personally, but I’m a little miffed professionally,” Patrick joked at the press conference.

McLaughlin will be sentenced June 14 and is required to cooperate as a condition of his plea. Attorney General Martha Coakley is also still investigating McLaughlin’s fundraising on Murray’s behalf.

The state Constitution does not provide a mechanism for an appointment to replace Murray, meaning that Patrick will operate without a lieutenant governor until his term expires in January 2015. Next in the line of succession is Secretary of State William F. Galvin, who will serve as acting governor when Patrick is out of state.

The Worcester group reached out to Murray about a month and a half ago, he said. Murray, who worked in the chamber’s mailroom while in high school, said he hired a private attorney to consult with the state Ethics Commission and informed Patrick of the opportunity “a few weeks after” the initial inquiry.

The chamber’s executive committee voted Thursday to pursue Murray and extended an offer on Friday, he said. On Tuesday, he filed a disclosure of the appearance of a conflict of interest with the Ethics Commission. He said Wednesday he was unsure whether he would register as a lobbyist, but would adhere to state ethics laws.

Worcester political and business circles started buzzing late Tuesday about the prospect of Murray, who has remained popular in the area after three terms of mayor, taking the chamber post. Many in the region feel that Murray’s fate within the Patrick administration is symbolic of Worcester’s treatment at the hands of the state’s Boston-centered power structure.

Lou DiNatale, a Worcester-area based Democratic operative, said Murray’s tough sledding in Massachusetts politics is symbolic of what many in that city feel is the “continued Boston bias against Worcester.”

“What Tim Murray bumped into is the invisible shield that prevents Worcester political figures from breaking into Boston-based political world,” DiNatale said.

Paul J. Giorgio, a long time Worcester Democratic activist and publisher of the city’s Pulse Magazine, said Murray ran up against the “bias of the Boston big-shots.” He praised Murray for his leadership skills, saying the lieutenant governor would refocus the chamber on the changing face of Worcester’s economy.

“We’ve always been second to Boston, yet there’s a lot going on in biotech, medical research, video gaming, and energy.

Murray, too, addressed that dynamic, saying the capital has dominated “ the discourse, the focus, not only in the media but in this building, and I think we do a disservice to the whole state and quite frankly to the whole greater Boston area.”

Murray said the chance to avoid the hours of travel required by his current job and to spend more time with his wife and two young daughters also appealed to him.