Democratic congresswoman and "Squad" member Cori Bush has lost her primary race in Missouri, according to US media projections.
Wesley Bell, a St Louis prosecutor, will instead be the party's candidate in the state's first congressional district this November.
Ms Bush came to prominence as an organiser in the Black Lives Matter movement and, after taking office in 2021, as one of the "Squad" of Democratic members of the House known for supporting progressive causes.
She has been a vocal critic of Israel's war in Gaza, with pro-Israel groups spending more than $10m (£7.9m) on efforts to unseat her in the primary.
Projections from both the Associated Press news agency and NBC News suggest Mr Bell is on track to win the vote with 51% of ballots cast, compared to Ms Bush's 46%.
The district is a strongly Democratic area and Mr Bell will be expected to hold it at the coming election.
Almost all the money spent in campaigning against Ms Bush reportedly came from the American Israel Public Affairs Committee (Aipac). Aipac is a pro-Israel lobbying group and has vowed to spend over $100m to unseat progressive lawmakers who have spoken out against the war in Gaza, Politico reported.
It marks the second loss for the Squad - a group of nine progressive lawmakers in the US House of Representatives - in recent months.
In June, more than $15m was put into a successful bid to oust Jamaal Bowman, another critic of Israel, from his seat in New York. The figure was the most spent in any House primary in history. Mr Bowman was ousted just weeks after he was censured for pulling a fire alarm while the House was in session.
Speaking to CBS News, the OceanNewsUK's US news partner, ahead of the vote, Mr Bell accused Ms Bush of "not doing her job".
"She is not working with others, and it's hurting our district."
Ms Bush defended her record to the outlet: "My community knows who I am. They know that I am going to fight for the people in the streets."
Less than two weeks after the 7 October attacks, Ms Bush introduced a resolution calling for a ceasefire and humanitarian aid.
The attacks, carried out by Hamas and other armed militant groups saw around 1,200 people killed in Israel and another 251 taken to Gaza as hostages.
In response, Israel declared a "complete siege" on Gaza, cutting off supplies of electricity, food, fuel, and water. To date, more than 39,600 people have been killed during Israel's military campaign in Gaza, according to the Hamas-run health ministry.
Ms Bush also boycotted a joint address to Congress by Israeli Prime Minister Benjamin Netanyahu in July, calling him a war criminal and saying he was at the forefront of a genocide. Dozens of House and Senate Democrats boycotted Mr Netanyahu's address.
In a statement ahead of the vote Ms Bush accused Mr Netanyahu of perpetrating a "genocide" in Gaza and claimed Congress was "actively celebrating" his actions.
Ms Bush has also been investigated by the justice department, House ethics committee and Federal Elections Commission for her campaign spending, mostly over allegations that she improperly paid her husband, a security guard, for protection.
She previously said any claims she had misused federal funds were "simply false".
