Jackson constantly found herself caught between administration pledges to solve thorny 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 of Michigan, 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, the agency's first black administrator and a chemical engineer, 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.
Despite the opposition, which former EPA chiefs have said is the worst they have seen against the agency, Jackson still managed to take significant steps that will improve air quality and begin to curb global warming.
"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 will leave sometime after President Barack Obama delivers his State of the Union address, typically 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," he said.
Environmental activist groups and other supporters lauded Jackson for the changes she was able to make, but industry representatives said some may have come at an economic cost. Groups also noted that she leaves a large, unfinished agenda.
"There has been no fiercer champion of our health and our environment than Lisa Jackson, and every American is better off today than when she took office nearly four years ago," said Frances Beinecke, president of the Natural Resources Defense Council. But she noted that Jackson's successor will inherit an unfinished agenda, including the need to issue new health protections against carbon pollution from existing power plants.
Sen. Tom Carper, D-Del., chairman of the Senate's subcommittee on clean air, called Jackson's tenure a "breath of fresh air" and credited her for setting historic fuel economy standards for cars and trucks, and for finalizing clean air standards.
But Scott Segal, director of the Electric Reliability Coordinating Council, said Jackson presided over some of the most expensive environmental rules in EPA history.
"Agency rules have been used as blunt attempts to marginalize coal and other solid fossil fuels and to make motor fuels more costly at the expense of industrial jobs, energy security, and economic recovery," Segal said. "The record of the agency over the same period in overestimating benefits to major rules has not assisted the public in determining whether these rules have been worth it."
Other environmental groups, however, praised Jackson's clean air efforts.
"Notwithstanding the difficult economic and political challenges EPA faced, her agency was directly responsible for saving the lives of tens of thousands of Americans and improving the health of millions throughout the country," said S. William Becker of the National Association of Clean Air Agencies. "She will be sorely missed."
Larry Schweiger, head of the National Wildlife Federation, cited her climate change work and efforts to reduce carbon pollution.
Environmental groups had high expectations for the Obama administration after eight years of President George W. Bush, a Texas oilman who rebuffed agency scientists and refused act 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 then abandoned by the Senate as economic concerns became the priority. The concept behind the bill, referred to as cap-and-trade, would have established a system where power companies bought and sold pollution rights.
"That's a revolutionary message for our country," Jackson said at a Paris conference shortly after accepting 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 him 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 race.
Associated Press writers Lolita C. Baldor and Pauline Jelinek contributed to this report.