Johnny Isakson, a Georgia Republican who succeeded Newt Gingrich in the House of Representatives, and in 15 years in the Senate was a moderate conservative, often championing bipartisan cooperation, until his resignation for health reasons in 2019, died on Sunday at his home in Atlanta. . He was 76.

His death was confirmed by the Isakson Initiative, which he founded to raise money for research into neurocognitive diseases. It did not specify a cause, but when he resigned, Senator Isakson had cited progressive Parkinson’s disease and surgery to remove a growth on a kidney.

Mr. Isakson made a fortune as a real estate executive before going into politics at 32. He served 17 years in the Georgia Legislature, lost a race for governor and another to succeed Senator Sam Nunn, a retiring Democrat who had been in office for 25 years. As a consolation, the governor named Mr. Isakson to head the state Board of Education. It seemed his political career was over.

But Mr. Gingrich, the mercurial House speaker from Georgia, was facing a revolt in his caucus over midterm election losses. He resigned as speaker and announced that he would not take his seat for an 11th term starting in January 1999. A month later, Mr. Isakson, well-liked in the state for his legislative and education work, won a special election and took Mr. Gingrich’s seat.

In the House, Mr. Isakson joined the education committee and became a strong advocate of President George W. Bush’s No Child Left Behind law, which required states to test all elementary and high school students and close gaps in reading and math achievement. He was photographed with the president in the Oval Office and aboard Air Force One, and was soon a national notable.

Affirming his growing popularity, Mr. Isakson won re-election to his first full term in 2000 with 75 percent of the vote and his second term in 2002 with 80 percent.

In 2003, another opportunity arose. Senator Zell Miller, a Georgia Democrat and former governor, chose not to run for re-election. Mr. Isakson jumped into the race and easily defeated the Democratic candidate, Representative Denise Majette, for a Senate seat.

“Johnny Isakson’s decisive election to the U.S. Senate completes the Republican sweep of Georgia, giving the state two Republican senators for the first time in modern history,” Georgia Trend Magazine said. “Well respected among Democrats and Republicans, cut from the same cloth as longtime Senator Sam Nunn, he has a reputation as a hard-working bridge-builder who prefers to spend his time finding areas of agreement rather than dwelling on differences.”

To be sure, Mr. Isakson voted with his conservative Republican allies in the vast majority of Senate roll calls. He opposed the Affordable Care Act and gay marriage, and defended gun rights. He identified with opponents of abortion, and in 2017 made a dramatic Senate entrance in a wheelchair to cast a deciding vote against Planned Parenthood funding. He voted for most of President Donald J. Trump’s cabinet choices.

But his exceptions to the conservative line, while far less numerous, were often striking. Rebutting his party in 2010, he and a dozen other Republican senators helped ratify a strategic arms reduction treaty negotiated by the Obama administration with Russia. It cut in half the number of strategic nuclear missile launchers on both sides.

Mr. Isakson, normally a reserved Republican, was often at odds with Mr. Trump in his 2016 presidential campaign, especially over his refusal to distance himself from the former Ku Klux Klan leader David Duke.

As the nation paid tribute to the Rev. Dr. Martin Luther King Jr. on his national holiday in 2018, members of the King family gathered at his Ebenezer Baptist Church in Atlanta and denounced Mr. Trump, who had often used what were widely regarded as racist slurs and who, only days earlier, had reportedly used shocking terms to describe Haiti and African countries.

Mr. Isakson, in a statement, called it a day to “honor and remember the leadership and wisdom of Dr. Martin Luther King Jr., whose legacy continues to make a positive difference in the lives of many people in our state and around the world.” As for Mr. Trump’s comments on Haiti and African nations, he said: “That is not the kind of statement the leader of the free world ought to make, and he ought to be ashamed of himself.”

In March 2019, seven months after Senator John McCain died, Mr. Trump was still mounting posthumous attacks on the Arizona maverick, who had been a Navy pilot and prisoner of war for five years in Vietnam. Before a military audience in Lima, Ohio, Mr. Trump, who had never served in the military, blamed him for “a war in the Middle East that McCain pushed too hard.”

“It’s deplorable what he said,” Mr. Isakson told Georgia Public Broadcasting. “It will be deplorable seven months from now if he says it again, and I will continue to speak out.”

A few months later, Mr. Isakson announced that he would resign his Senate seat at the end of 2019, halfway through his third term, for health reasons.

He had been a dominant voice for passage of a multibillion-dollar overhaul of the veterans’ health care system, and in efforts to resolve partisan fights over allocating relief funding for several natural disasters in 2018. And he remained popular with voters — re-elected without opposition in 2010, and in 2016 with 55 percent of the ballots — and with his Senate colleagues.

“Not only is Johnny a diligent and successful legislator, he is one of the kindest, most thoughtful senators,” Senator Chuck Schumer of New York, the Democratic leader, said after Mr. Isakson announced his resignation. “Independent of any party or politics, everyone will miss Johnny.”

John Hardy Isakson was born in Atlanta on Dec. 28, 1944, the son of Edwin and Julia (Baker) Isakson. His father founded Northside Realty in Atlanta, which grew into one of the nation’s most successful real estate companies.

After high school, Johnny earned a bachelor’s degree in business administration in 1966 from the University of Georgia. He then founded the first Cobb County branch of his father’s real estate firm. In 1979, he became president of the company, a post he held for 22 years.

In 1968, he married Dianne Davison. They had three children: John, Julie and Kevin. They all survive him, as well as nine grandchildren.

He served 14 years in the Georgia House of Representatives from 1976 to 1990, and three years in the State Senate from 1993 to 1996. His family attended a Methodist church and he taught Sunday school for 30 years.

A social high point of his Senate years was an annual barbecue lunch he hosted for colleagues on both sides of the aisle. As his 20-year Washington tenure ended in December 2019, an outpouring of tributes from voters and Senate colleagues prompted a piece of advice from Mr. Isakson.

“I’m big on bipartisanship,” he said. “Whether you’re Black or white, Republican or Democrat, whatever it might be, find a way to find common ground. Give it a chance to work.

“Bipartisanship,” he added, is “a state of being.”