Jackson, the agency's first black administrator, constantly found herself caught between administration pledges to solve controversial environmental problems and steady resistance from Republicans and industrial groups who complained that the agency's rules destroyed jobs and made it harder for American companies to compete internationally.
The GOP chairman of the House Energy and Commerce Committee, Rep. Fred Upton, said last year that Jackson would need her own parking spot at the Capitol because he planned to bring her in so frequently for questioning. Republican presidential nominee Mitt Romney called for her firing, a stance that had little downside during the GOP primary.
Jackson, 50, a chemical engineer by training, did not point to any particular reason for her departure. Historically, Cabinet members looking to move on will leave at the beginning of a president's second term.
"I will leave the EPA confident the ship is sailing in the right direction, and ready in my own life for new challenges, time with my family and new opportunities to make a difference," she said in a statement. Jackson gave no exact date for her departure, but will leave after Obama's State of the Union address in late January.
In a separate statement, Obama said Jackson has been "an important part of my team." He thanked her for serving and praised her "unwavering commitment" to the public's health.
"Under her leadership, the EPA has taken sensible and important steps to protect the air we breathe and the water we drink, including implementing the first national standard for harmful mercury pollution, taking important action to combat climate change under the Clean Air Act and playing a key role in establishing historic fuel economy standards that will save the average American family thousands of dollars at the pump, while also slashing carbon pollution."
Environmental groups had high expectations for the Obama administration after eight years of President George W. Bush, a Texas oilman who rebuffed the agency's scientists and refused to take action on climate change. Jackson came into office promising a more active EPA.
But she soon learned that changes would not occur as quickly as she had hoped. Jackson watched as a Democratic-led effort to reduce global warming emissions passed the House in 2009 but was abandoned by the Senate as economic concerns became the priority. The concept behind the bill, referred to as cap-and-trade, would have set up a system in which power companies bought and sold pollution rights.
"That's a revolutionary message for our country," Jackson said at a Paris conference a few months after taking the job.
Jackson experienced another big setback last year when the administration scrubbed a clean-air regulation aimed at reducing health-threatening smog. Republican lawmakers had been hammering the president over the proposed rule, accusing his administration of making it harder for companies to create jobs.
She also vowed to better control toxic coal ash after a massive spill in Tennessee, but that regulation has yet to be finalized more than four years after the spill.
Jackson had some victories, too. During her tenure, the administration finalized a new rule doubling fuel efficiency standards for cars and light trucks. The requirements will be phased in over 13 years and eventually require all new vehicles to average 54.5 mpg, up from 28.6 mpg at the end of last year.
She shepherded another rule that forces power plants to control mercury and other toxic pollutants for the first time. Previously, the nation's coal- and oil-fired power plants had been allowed to run without addressing their full environmental and public health costs.
Jackson also helped persuade the administration to table the controversial Keystone XL pipeline, which would have brought carbon-heavy tar sands oil from Canada to refineries in Texas.
House Republicans dedicated much of their time this past election year trying to rein in the EPA. They passed a bill seeking to thwart regulation of the coal industry and quash the stricter fuel efficiency standards. In the end, though, the bill made no headway in the Senate. It served mostly as election-year fodder that appeared to have little impact on the presidential election.