The Democrat said in a statement that she decided against a reelection bid so she could avoid further politicizing her fight with the state's Republican Legislature over school funding.
Perdue becomes the third Democratic incumbent to decide against seeking a new term this year. Eleven gubernatorial posts are up for grabs in 2012, eight of which are currently held by Democrats.
Previously the state's lieutenant governor for two terms, Perdue won a narrow victory in 2008 over then-Charlotte Mayor Pat McCrory, a win credited in part to the strength of Barack Obama's strong organization in the state.
But her poll numbers have long been in perilous terrain for an incumbent. Perdue's statement acknowledged that "difficult economic times" have demanded "many difficult decisions."
"I have had to make painful budget cuts in important areas of government. But I believe I have approached this challenge in a way that is consistent with my values," she said.
McCrory is already running again for the GOP and looked to be a favorite in a November rematch against Perdue, which would end two decades of Democratic control of the office.
"It's never been more clear that North Carolina needs a Republican governor who will bring fresh ideas and a new perspective to the governor's office," Republican Governors Assn. executive director Phil Cox said in a statement.
National Republicans were also eager to spin Perdue's decision as a blow to Democrats and President Obama, since the party's national convention is to be held in Charlotte this September. Perdue is also vice chair of the Democratic Governors Assn.
It was not clear who might be able to step up for Democrats in Perdue's place. Three-term Atty. Gen. Roy Cooper said he still plans to seek reelection, the Associated Press reported. Still, the Democratic Governors Assn. said it would be "fully engaged" to make sure the seat stays Democratic.
"The DGA believes that North Carolina remains a strong opportunity for Democrats in 2012, especially now that Pat McCrory has walked in lock-step with the Republican leadership's efforts to cut funding for North Carolina public schools and colleges," DGA Chairman Martin O'Malley of Maryland said in a statement.
Another North Carolina Democrat, U.S. Rep. Brad Miller, also said Thursday that he would not seek reelection. Redistricting would have forced him to have to challenge another Democratic incumbent in a primary.