Judges at the Court of Cassation yesterday also quashed all charges against Knox's Italian ex-boyfriend Raffaele Sollecito after 10 hours of deliberations in Rome.
"I am tremendously relieved and grateful for the decision of the Supreme Court of Italy," Knox said in a statement from her home in Seattle.
The 27-year-old, who served four years in prison before being freed on appeal in 2011, added: "The knowledge of my innocence has given me strength in the darkest times of this ordeal."
"Finally I can resume my life," he said. "I still can't quite believe it. Finally I will no longer have to spend all my time with legal papers. I can return to normal."
The shock verdict was greeted with chaotic, jubilant scenes in the great hall of the Roman courthouse.
Chairs went flying as Sollecito's lawyer Giulia Bongiorno reacted to the shock verdict by shouting "yes, yes, yes" and leaping up and into the arms of a colleague.
One of Knox's lawyers, Luciano Girgha, admitted he had been surprised by the verdict, but said it had restored the battered credibility of Italy's judicial system.
"It was a brave decision, it has renewed my faith in the system," Girgha said.
"It went beyond my wildest expectations, I'm super happy for Amanda. She has finally got her life back. She always insisted she was innocent."
Knox and Sollecito believed they had been freed to resume their normal lives when they were first acquitted in 2011.
But that decision was found to be flawed by the Court of Cassation in 2013, leading to a retrial in Florence which reinstated the initial convictions last year and increased Knox's sentence to 28 years and six months.
Knox's conviction for slander, which relates to a statement in which she tried to incriminate a Congolese bar owner for the murder, was not overturned but the time she served in prison more than covers the sentence for that. Knox says that statement was made under duress and her lawyers may want to pursue a case for malicious prosecution.
Had the convictions been upheld, Knox would have almost certainly faced extradition, which she had vowed to resist.
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