"It's time for me to go do something else," DeLay, who denied any wrongdoing in an interview with Fox News, said on Tuesday.
DeLay's announcement came as a surprise, but a Republican party leadership aide said he was "long expected to do the right thing for his party".
The US politican from Texas had a day earlier informed George Bush, the US president, and House Republican leaders of his decision.
Republicans have been trying to stave off what is expected to be a strong challenge by Democrats to recapture control of Congress in November elections.
Democrats have sought to make DeLay and Republican ethical scandals an issue in the effort and Republicans shared DeLay's hope that a new candidate in his district would give the party a better chance to keep the seat in November.
DeLay, 58, blamed politics for his woes, which have included an indictment in Texas on campaign-finance charges last year that forced him to resign as majority leader, and an expanding lobbying scandal in Washington that has ensnared two former aides.
Ronnie Earle, the Travis County district attorney, said despite DeLay's decision to leave Congress, the charges against him in Texas would remain.
"DeLay's ultimate fate will be decided by the public acting through a jury," Earle said.
'Proud of the past'
DeLay's announcement came 12 years after he helped Republicans capture control of the House for the first time in 40 years.
"I am proud of the past. I am at peace with the present," DeLay said in an address posted on his website.
"Because I care so deeply about this district and the people in it, I refuse to allow liberal Democrats an opportunity to steal this seat with a negative, personal campaign," DeLay said.
"I refuse to allow liberal Democrats an opportunity to steal this seat with a negative, personal campaign ... so today, I am announcing my intention to resign"
"So today, I am announcing my intention to resign my seat in the House," said DeLay, adding he would leave by mid-June.
Top House Republicans, many of whom owe a political debt to DeLay, appeared together before TV cameras to praise him, but declined to take any questions.
Last month, DeLay beat three relatively unknown Texas Republican primary foes. But he faced what promised to be a tougher challenge in November from Democrat Nick Lampson, a former House member.
At the White House, Bush said of DeLay: "I wish him all the very best and I know he's looking to the future."
First elected to the House in 1984, DeLay, nicknamed The Hammer, was rebuked by the House ethics committee on three separate matters in 2004 and stepped down as House majority leader in September after being indicted in Texas.
The second of two former DeLay aides pleaded guilty last week in the federal investigation surrounding convicted lobbyist Jack Abramoff and have agreed to co-operate with prosecutors.