Knox collapsed in tears after the verdict overturning her 2009 conviction was read out. Her co-defendant, Italian Raffaele Sollecito, also was cleared of killing 21-year-old Meredith Kercher in 2007.
The Kercher family looked on grimly and a bit dazed as the verdict was read out by the judge after 11 hours of deliberations by the eight-member jury. Outside the courthouse, some of the hundreds of observers shouted "Shame, shame!"
Yet inside the frescoed courtroom, Knox's parents, who have regularly traveled from their home in Seattle to Perugia to visit the 24-year-old over the past four years, hugged their lawyers and cried with joy.
"We've been waiting for this for four years," said one of Sollecito's lawyers, Giulia Bongiorno.
The judge upheld Knox's conviction on a charge of slander for accusing bar owner Diya "Patrick" Lumumba of carrying out the killing. He set the sentence at three years, meaning for time served. Knox has been in prison since Nov. 6, 2007.
Prosecutors can appeal the acquittal to Italy's highest court. There was no word late Monday if they planned to do so.
In Seattle, about a dozen Knox supporters were overjoyed that she has been cleared of the murder conviction.
"She's free!" and "We did it!" they shouted at a hotel where they watched the court proceedings on TV.
Earlier Monday, Knox tearfully told the court she did not kill her roommate. Knox frequently paused for breath and fought back tears as she spoke in Italian to the eight members of the jury in a packed courtroom, but managed to maintain her composure during the 10-minute address.
"I've lost a friend in the worst, most brutal, most inexplicable way possible," she said of the 2007 murder of Kercher, who shared an apartment with Knox when they were both students in Perugia. "I'm paying with my life for things that I didn't do."
Knox and Sollecito, Knox's former boyfriend from Italy, were convicted in 2009 of sexually assaulting and murdering Kercher, who was stabbed to death in her bedroom. Knox was sentenced to 26 years in prison, Sollecito to 25. They both deny wrongdoing.
"I never hurt anyone, never in my life," Sollecito said Monday in his own speech to the jury.
Hundreds of eager observers gathered outside the courthouse ahead of the highly anticipated announcement, joining television vans that have been camped out for more than a week. One hundred reporters were being allowed into the subterranean courtroom.
Observers lined the street leading to the courthouse, taking pictures as the two vans carrying Knox and Sollecito from the prison to the court passed by.
Kercher's mother, sister and a brother traveled to Perugia for the verdict. They had expressed worry over the possibility of an acquittal but told reporters as deliberations were under way that they hoped the jury would do the right thing and not be influenced by the media's focus on the case.
"As long as they decide today based purely on the information available to them and they don't look into the media hype, I think justice will be found," the victim's sister, Stephanie Kercher, told reporters. She said the family was satisfied with the original verdicts.
She lamented that Meredith had been "most forgotten" in the media circus surrounding the case, with news photos more frequently showing Knox and Sollecito than "Mez" - the victim's nickname. "It's very difficult to keep her memory alive in all of this," she said.
The family, however, said it could understand the Knox family's media campaign.
"They fully believe in her innocence. You can't blame them for that," said Lyle Kercher, the victim's brother. "But it's obviously hard for us."
As the verdict was broadcast live, hundreds of reporters and camera crews filled the underground, frescoed courtroom before Knox's address, while police outside cordoned off the entrance to the tribunal.
The trial has captivated audiences worldwide: Knox and Sollecito had been convicted of murdering Meredith in what the lower court said had begun as a drug-fueled sexual assault.
Knox insisted Monday that she had nothing to do with the murder and that Kercher was a friend who was always nice to her. Gesticulating, at times clasping her hands together, the American said she has always wanted justice for Kercher.
"She had her bedroom next to mine, she was killed in our own apartment. If I had been there that night, I would be dead," Knox said. "But I was not there."
"I did not kill. I did not rape. I did not steal. I wasn't there," Knox said.
After the morning court session, Knox was relaxing in the prison chapel, playing guitar and singing as she awaited the verdict, according to an Italian lawmaker who visited her in prison Monday.
"These are obviously the most difficult hours," Rocco Girlanda, who has spearheaded a campaign in Italy in support of Knox, told The Associated Press. "The time never seems to pass."
Also convicted in separate proceedings was Rudy Hermann Guede, a small-time drug dealer and drifter who spent most of his life in Italy after arriving here from his native Ivory Coast. Guede was convicted in a separate fast-track procedure and saw his sentence cut to 16 years in his final appeal.
Lawyers for Knox and Sollecito believe Guede was the sole killer, but the prosecution and a lawyer for the Kercher family say that bruises and a lack of defensive wounds on Kercher's body prove that there was more than one aggressor holding her into submission.
Knox said she had nothing more than a passing acquaintance with Guede, who played basketball at a court near the house, and didn't even know his name. Sollecito, who addressed the court before Knox, told jurors that he did not know Guede at all.
Sollecito was anxious as he addressed the court, shifting as he spoke and stopping to sip water. He said prior to the Nov. 1, 2007 murder was a happy time for him, he was close to defending his thesis to graduate from university and had just met Knox.
The weekend Kercher was murdered was the first the pair planned to spend together "in tenderness and cuddles," he said.
At the end of his 17-minute address, Sollecito took off a white rubber bracelet emblazoned with "Free Amanda and Raffaele" that he said he has been wearing for four years.
"I have never taken it off. Many emotions are concentrated in this bracelet," he said. "Now I want to pay homage to the court. The moment to take it off has arrived."
Patricia Thomas contributed.