Sergeant Robert Bales faces charges including 16 counts of murder, six of attempted murder and seven of assault over the massacre in southern Afghanistan in March last year.
The 39-year-old appeared at Joint Base Lewis-McChord in Washington state to enter his plea over the killings, which further strained already tense US-Afghan ties.
Seventeen of the 22 victims were women or children and almost all were shot in the head. Prosecutors called in November for him to face the death penalty, setting a provisional date for court-martial in September.
His lawyer John Browne announced last week that he had reached "an agreement with the military to take the death penalty off the table if (Bales) he will plead" guilty.
Asked if Bales was sorry, Browne said: "Absolutely. And I think that will become clear as the process goes forward. He's very relieved that the death penalty is not on the table."
"And then he'll have a sentencing trial in September to determine whether he can get life with parole or whether he will get life without parole," Browne said in video interview.
The plea bargain deal is likely to anger families of the victims who originally wanted him to face justice, and potentially a death penalty, in Afghanistan.
Bales allegedly left his base in the Panjwayi district of southern Kandahar province on the night of March 11, 2012, to commit the killings, which included nine children. Bales allegedly set several of their bodies on fire.
At a pre-trial hearing in November, Bales's family insisted he was innocent until proven guilty, calling him "courageous and honorable," while his lawyer raised questions about the role of alcohol, drugs and stress in the tragedy.
But prosecutors lashed the "heinous and despicable" alleged massacre during an eight-day hearing, details of which were given at the military base south of Seattle.
Prosecutors at the so-called Article 32 pre-trial hearing alleged that Bales left the base twice to carry out the killings, returning in between and even telling a colleague what he had done.
The hearing included three evening sessions -- daytime in Afghanistan -- to hear testimony by video conference from Afghan victims and relatives of those who died.
In a statement read out by the soldier's sister Stephanie Tandberg after last year's hearing, the family said it had yet to learn the how, why and what of the incident.
"Much of the testimony was painful, even heartbreaking, but we are not convinced the government has shown us the truth, the whole truth and nothing but the truth about what happened that night," it said.
"As a family, we all grieve deeply for the Afghani families who lost their loved ones on March 11, but we must all not rush to judgment.
"In America, due process means innocence is always presumed unless and until a trial proves otherwise. There has been no trial yet, and our family member is presumed by law, and by us, to be innocent."
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