Issa, who joined the House in 2001, won re-election in 2016 by a half percentage point in a district that favored Democratic presidential nominee Hillary Clinton to President Donald Trump.
While Issa's ninth term will be his last, the Associated Press notes he left his mark by dogging then-President Barack Obama with probes into the 2012 killings of four Americans in Benghazi, Libya, and Internal Revenue Service audits of conservative groups.
Issa released an announcement on his decision, in which he called his 18 years in Congress "the privilege of a lifetime".
Issa was first elected to the House in 2000, and served as chairman of the House Oversight Committee from 2011 to 2015.
Rep. Darrell Issa, a California Republican whose seat was considered vulnerable in the midterm elections, announced Wednesday that he will retire from Congress at the end of this year. Hillary Clinton won the district by almost 7 points in the 2016 election.
On Tuesday one of Issa's California colleagues, Rep. Ed Royce, also announced that he would not seek reelection.
Early in the 2018 election cycle, Democrats identified the Orange County-area Republican seats as top targets.
"I am forever grateful to the people of San Diego, Orange and Riverside counties for their support and affording me the honor of serving them all these years", Issa wrote in a statement Wednesday. Royce is also from California.
Issa became the second California Republican to retire this week. For a year, hundreds of activists have appeared weekly outside of Issa's office to protest.
Republicans, meanwhile, say they will benefit from the fight between the Democrats seeking to claim the seat.
"We look forward to facing whoever limps out of the Democrats' battle royal: black and blue, and broke", Rep. Steve Stivers, R-Ohio, the NRCC's chairman, said in a statement.
"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.