Issa, one of the wealthiest members of Congress and among the best-known due to his reputation as a conservative attack dog, is bowing out of what would have been one of the nation's most hotly contested congressional races.
He told reporters Wednesday as he left the House floor that "it was time," but that he plans to stay involved in politics and spend his own money helping Republicans.
"I'm going to be 65 and happily looking forward to doing other things," Issa said. "I intend on staying very involved in both contributing my time and money because I believe in the issues I came here 18 years ago so there's nothing changing."
He nearly lost his seat in 2016, besting Democrat Douglas Applegate -- among the four Democrats running this year -- by less than a percentage point. It's among seven Republican-held districts in California that Hillary Clinton won that year, carrying Issa's by 8 percentage points.
Those results made Issa perhaps the most endangered Republican member of Congress heading into the 2018 election cycle.
But he'd maintained he intended to run for re-election, telling CNN in November that hew as 100% certain he'd seek another term. "Yeah, I enjoy the job I'm doing," he said then.
On Wednesday, Issa downplayed President Donald Trump's unpopularity as a factor in the upcoming midterms.
"The reality is that America is better for the last year of this administration and this Congress," Issa said.
First elected in 2000, Issa's retirement ends the career of a figure who rose to prominence during former President Barack Obama's tenure, after he took the helm of the House oversight committee following the GOP wave of 2010. He presided over contentious hearings into the attack on the US embassy in Benghazi, Libya, and on the Internal Revenue Service's targeting of conservative groups.
Orange County a 2018 battleground
Issa's decision not to run for re-election comes the same week that Rep. Ed Royce, the powerful chairman of the House Foreign Affairs Committee and another California Republican whose district includes parts of Orange County, announced his retirement.
Royce and Issa's districts are both in expensive television markets -- further stretching national Republicans who are on defense across dozens of districts in the 2018 midterm elections.
Early in the 2018 election cycle, Democrats identified the Orange County-area Republican seats as top targets.
The Democratic Congressional Campaign Committee hired local organizers in both Royce and Issa's districts in February 2017, and opened a regional office in Orange County for the first time in April.
In California, at the forefront of the Democratic resistance to President Donald Trump, the party has also seen an energized activist base fueled in part by the emergence of new organizations such as Indivisible.
Those activists have protested weekly outside Issa's Vista, California, district office -- leading to a strange scene in May
in which Issa stood on his rooftop, looking down at the protesters below.
Candidates to replace Issa
Diane Harkey, a former state lawmaker who is now an elected Republican representative on the California State Board of Equalization, a tax administration board, is poised to enter the race, a Republican source said.
Another Republican source identified California state assemblyman Rocky Chavez and former assemblyman Scott Baugh as other potential candidates.
Issa said "there are plenty of people that fit the district just fine" and predicted reporters would be covering just as many Republicans entering the race as Democrats already competing in the primary.
"I feel like I'm going out on top at a time when a generic Republican's going to win my district and I'm going to support the nominee on my side and then I'm going to continue to be very active," he said.
Applegate, a retired Marine colonel, and three other Democrats are running: Businessman Paul Kerr, environmental attorney Mike Levin and Sara Jacobs, who worked in foreign policy at the State Department and United Nations.
California holds a jungle primary, which means the top two finishers -- regardless of party -- advance to the general election.
"California Republicans clearly see the writing on the wall and realize that their party and its priorities are toxic to their re-election chances in 2018," Democratic Congressional Campaign Committee spokesman Drew Godinich said.
In a statement, Rep. Steve Stivers, the National Republican Congressional Committee chairman, said the GOP hopes an expensive and divisive Democratic contest in California's primary will allow the party to hold the seat.
"While Democrats fight with each other, Republicans will focus on fighting Democrats -- and that's how we plan to win," Stivers said.