"In 1974, I announced my first campaign for Congress. Today, I am announcing that I have run my last campaign. I will not seek reelection to the Congress and will leave after 40 years in office at the end of this year," Waxman said in a statement.
He said in his statement that during his career, he strived to be an advocate for "the poor, the sick, and the powerless who need a champion in Congress."
"I have learned that progress is not always easy. It can take years of dedication and struggle. But it's worth fighting for," Waxman said.
The Los Angeles native has been a congressional force on clean air and expansion of Medicaid. He also pushed for investigations into the tobacco industry and was instrumental in getting President Barack Obama's health care overhaul completed.
"As I reflect on my career, I am filled with gratitude," Waxman said. "I am grateful for the support of my constituents, who have entrusted me to represent them and encouraged me to become a leader on national and international issues."
His legislative accomplishments also include a law that created the generic drug industry and food safety laws that created nutrition labels, removed pesticides from fruits and vegetables and made imported food safer.
"I never imagined I would be in the House for 40 years and be able to advance every issue I care deeply about. But in what feels like a blink of an eye, it has been 40 years and I've devoted most of my life to the House of Representatives," Waxman said.
Rep. Adam Schiff (D-Burbank) called Waxman "one of the giants of Congress -- smart, strategically savvy, dogged at oversight and a power to be reckoned with."
"His hand can be seen in almost every domestic achievement of the last few decades," Schiff said in a statement.
Waxman admitted in his statement that there are elements of Congress that he does not like.
"I abhor the extremism of the Tea Party Republicans. I am 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," Waxman said.
But he stressed that he was not leaving out of frustration, but rather to give somebody else a chance to make a mark in Congress.
"I have had a long career and an eventful one -- and I wouldn't trade any of it," Waxman said. "I woke each day looking forward to opportunities to make our country stronger, healthier, and fairer. And I will always be grateful for this honor and privilege."
The Associated Press contributed to this report.