"I shot Mr Thompson in Manhattan and he died," Mangione said.
He wore beige prison garb and spoke clearly and calmly as he read from a prepared statement laced with criticism of the US health insurance system.
Thompson's widow sat in the front row of the gallery with other members of his family.
When Mangione admitted to shooting Thompson, she choked up while two women seated next to her comforted her.
The guilty plea will avert a federal trial in the closely watched case over the killing of the 50-year-old UnitedHealthcare CEO, a brazen crime that was condemned by public officials but became emblematic of popular frustration with health insurance industry practices in the United States.
Mangione, 28, entered his plea without a deal with federal prosecutors, and there was no guarantee that taking responsibility would result in any leniency at sentencing.
Prosecutors said they would seek a sentence of life in prison - the maximum allowable - at his sentencing on December 18.
US District Judge Margaret Garnett is allowed to consider Mangione's decision to plead guilty as a mitigating factor when determining his punishment.
The federal guilty plea also allowed Mangione's lawyers to file a motion to dismiss separate state murder and weapons charges ahead of a trial in that case, arguing that he should not have to be punished for the same conduct twice under New York's law prohibiting double jeopardy.
Jamie McDonald, the Manhattan US Attorney, said his office had made no accommodations or concessions to Mangione.
"No grievance or ideological cause can ever justify murder," McDonald told reporters.
Thompson's family said in a statement that the plea marked an "important step toward justice".
"We look to the court to ensure that sentencing reflects the severity of this crime," Thompson's family said.
Thompson led UnitedHealth Group's insurance unit before he was shot dead in the early morning of December 4, 2024, outside a hotel where an investor conference was taking place.
Graphic footage of the killing and a five-day manhunt for a suspect made the case a media fixture and social media sensation.
Mangione was arrested in Pennsylvania.
Mangione said in his courtroom statement that he navigated obstacles with his insurance after suffering a broken back, without providing details.
Mangione said he emailed UnitedHealthcare leadership seeking details of its 2024 investor conference, pretending to be an investor managing more than $US50 billion ($A71 billion) in assets.
He said he received a response within an hour, which he said was quicker than previous interactions with insurers.
"I observed that the annual conference of America's largest health care organisation with the stated mission to make the health system work better for everyone would be attended by company executives, the board of directors and hundreds of investors - not doctors, nurses and patients," Mangione said.
Mangione said he then used a 3-D printer to make part of a gun and travelled to New York with the intent of killing Thompson.
UnitedHealth Group said in a statement, "We are grateful to law enforcement for bringing Brian's murderer to justice."
Mangione had previously pleaded not guilty in April 2025 to federal murder, weapons and stalking charges.
Garnett threw out the murder and weapons charges over legal technicalities in a surprise ruling in January 2026.
The decision eliminated the possibility that Mangione would face the death penalty in the federal case.
Mangione separately pleaded not guilty in December 2024 to state terrorism, murder, weapons and forgery charges brought by Manhattan District Attorney Alvin Bragg.
The terrorism charges were thrown out by a judge in September 2025.
A trial in the state case is scheduled for September 8 before Justice Gregory Carro in Manhattan.
Mangione would face 25 years to life in prison if convicted of second-degree murder.
