The decision is the final ruling in the case relating to the 2007 murder.
Meredith Kercher, 21, was found dead in a Perugia flat she shared with Amanda Knox.
Amanda Knox and her Italian ex-boyfriend were found guilty in 2009, then freed in 2011 after the convictions were overturned. They were reinstated by another court in 2014.
Raffaele Sollecito and Amanda Knox had always maintained their innocence and the decision by the Court of Cassation puts an end to their long legal battle.
The reasoning behind the decision will be made public in 90 days.
Amanda Knox, 27, said she was “full of joy” after hearing the verdict.
“I’m still absorbing the present moment,” she said, speaking outside her mother’s house in Seattle, expressing thanks “for the justice I’ve received and for the support I’ve had from everyone”.
Amanda Knox added: “Meredith was my friend, she deserved so much in this life.”
The lawyer for Ms Kercher’s family, Francesco Maresca, has expressed his disappointment with the verdict.
“I think that it’s a defeat for the Italian justice system,” he told the Associated Press news agency.
Meredith Kercher’s mother has been quoted by the Press Association as saying that she is “surprised and very shocked” by the acquittals.
Days after the killing, Amanda Knox and her boyfriend at the time, Raffaele Sollecito, 31, were arrested.
They were convicted of murder in 2009 by a court in Perugia.
In 2011, a jury cleared both defendants of the charge, after doubts were raised over the handling of DNA evidence.
A retrial was ordered after prosecutors argued that important evidence had been disregarded. In 2014, the guilty verdict was reinstated.
Another man, Rudy Hermann Guede, born in Ivory Coast, was also convicted in a separate trial and is serving a 16-year sentence for his role in the murder.
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