"It's time for someone else to have the chance to make his or her mark," the liberal California Democrat said Thursday in a statement announcing he won't seek re-election.
Democrats and some Republicans saluted Waxman for the breadth of his work, from policy to good government and more.
"Henry will leave behind a legacy as an extraordinary public servant and one of the most accomplished legislators of his or any era," President Barack Obama said in a statement.
By days' end, a prominent liberal activist was weighing a run to replace Waxman.
"I am strongly considering running," Sandra Fluke, the former Georgetown University law student who testified to congressional Democrats that she wanted her college health plan to cover her birth control. Radio personality Rush Limbaugh branded her a "slut," but later apologized. "I'll be making my decision soon," Fluke said Thursday.
Waxman himself said he never expected to serve in the House for so long.
"It has been an extraordinary experience," he said.
Not one, however, without a degree of disillusionment.
In his 3 1/2-page statement, Waxman explicitly condemned conservative House Republicans elected in 2010. "I abhor the extremism of the tea party," he said, adding he's "embarrassed that the greatest legislative body in the world too often operates in a partisan intellectual vacuum, denying science, refusing to listen to experts and ignoring facts."
But the mustachioed, bespectacled congressman made clear he's not running from the institution. He said he's not leaving out of frustration or because he thinks minority Democrats don't have a chance at regaining the House majority — his seat is likely to stay in Democratic hands. But he stopped short of predicting Democrats will retake the House in this year's midterm elections.
Waxman, 74, was elected during the post-Watergate class of 1974 and represents perhaps the nation's most glamorous district, including the movie star havens of Bel Air, Brentwood and Malibu. In addition to Fluke, Democratic state Sen. Ted Lieu said on his Facebook page he is "seriously looking at running" and would make an announcement Friday.
Over the next 20 terms in Congress, Waxman established himself as one of the House's leading liberals but one who would negotiate with other lawmakers to win passage of bills to help nursing home patients, HIV/AIDS victims and better ensure food safety. He worked with Utah Republican Sen. Orrin Hatch to pass major legislation that opened up the market for generic drugs, and collaborated closely for decades with the Republican who occupies Waxman's former seat at the helm of the House Energy and Commerce Committee.
"Despite our policy differences, Henry Waxman and I have forged a friendship and respect for one another," said the panel's current chairman, Rep. Fred Upton, R-Mich.
Few lawmakers have left a stamp on as many areas of the sprawling, complex health care system as Waxman has done. He chaired the Energy and Commerce Committee hearings that helped produce Obama's signature health care law.
Earlier in his career he chaired hearings exposing tobacco company executives as being well aware of the risks of cigarette smoking even as they crafted ad campaigns that featured characters appealing to children. That laid the foundation for closer federal regulation, which the industry at first fought, but now has grudgingly accepted.
Waxman was also a champion of environmental causes. He was one of the chief architects behind a 1990 upgrade to air pollution laws, and in 2009, along with then-Rep. Ed Markey, D-Mass., co-wrote the only bill to control global warming to have passed the House. The legislation, backed by the Obama administration, died in the Senate.