The conviction of Knox’s former boyfriend, Raffaele Sollecito, who was sentenced to 25 years in 2014 for the slaying, was also overturned.
Officials said Knox and Sollecito will not face new trials.
"I'm incredibly grateful for what has happened, for the justice I have received, for the support I have had from everyone," Knox said in front of her family's Seattle home Friday night."You saved my life."
Knox said she is still "absorbing" all the news. "I'm so grateful to have my life back," she said.
When asked whether she had any message for the Kercher family, Knox said, "Meredith was my friend ... she deserved so much in this life."
A separate statement from Knox was released earlier in the day after the court's decision was made.
“I am tremendously relieved and grateful for the decision of the Supreme Court of Italy,” Knox said in the statement. “The knowledge of my innocence has given me strength in the darkest times of this ordeal. And throughout this ordeal, I have received invaluable support from family, friends, and strangers. To them, I say: Thank you from the bottom of my heart. Your kindness has sustained me. I only wish that I could thank each and every one of you in person.”
Luca Maori, a lawyer representing Sollecito, said, “Raffaele was really happy. A court has finally had the courage to say ‘Enough.’”
Maori had called Sollecito from the steps of the court building to tell him “You have your whole life ahead of you now.”
The court upheld a three-year sentence for Knox for slander after she initially alleged that a Perugia barman, Patrick Lumumba, killed Kercher. She later retracted the allegation, saying she had been pressured into it by police. The sentence is likely to be canceled out by the four years Knox has already spent in jail in Italy, authorities said.
Kercher’s family hoped to see Knox’s and Sollecito’s convictions upheld. Their lawyer, Francesco Maresca, said Kercher’s mother, father, sisters and two brothers had come together at the family home in Coulsdon, Surrey, on Friday to await the outcome.
“I am very surprised by the verdict,” Maresca said. “There is not much to say. It is drastic and definitive.”
Knox, 27, and Sollecito, who turned 31 on Thursday, were first arrested in Perugia in November 2007 after Kercher, the 21-year-old roommate of Knox, was found semi-naked in a pool of blood with a deep knife wound to her neck.
Knox and Sollecito were sentenced in 2009 to 261/2 and 25 years in prison, respectively, but were freed when the verdict was reversed on appeal in 2011 after they had spent four years in prison.
Knox returned to the United States before the Rome high court ordered a new trial. The two were again found guilty, with Knox receiving a longer sentence: 28 years.
The case returned to the high court for what could have been a final sign-off, as required under Italian law, or a decision to send Knox and Sollecito back to trial again. Few people expected the court to definitively acquit the pair in the slaying.
The court’s decision leaves one man, Ivory Coast-born drifter Rudy Guede, in jail for Kercher’s slaying.
“There is just one assassin and he is in jail today,” Maori said after the ruling.
In a powerful two-hour speech in court Friday that may have swayed judges, Sollecito’s lawyer Giulia Bongiorno said Sollecito was a “Forrest Gump” caught up mistakenly in a murder investigation he did not understand.
She also cited numerous factual errors she said were contained in the sentencing document that backed up the sentences Knox and Sollecito were handed last year.
The ruling said that a female footprint had been found in blood in the room where Kercher was killed, whereas it was Guede’s footprint, she said. She added the ruling wrongly claimed no one had entered the room between a first and a second search, when Kercher’s bra-clasp was found, allegedly covered with Sollecito’s DNA. “Thirty-five people entered that room,” she said.
She pointed out that judges had acknowledged that the bra clasp, which constituted the “main proof” against Sollecito, might have been given a “kick” by investigators before it was finally found.
Bongiorno also asked how Knox had not left a DNA trace in the room if she had killed Kercher. “Only dragonflies do not leave a trace,” she said.
The errors in the sentence, she said, “were of colossal proportions.”
Describing the way investigators handled evidence, she said: “If you take the Bible and divide it into many parts you can put together a pornographic book from the pieces.”
After the court decision Friday, the Knox family issued a statement thanking everyone who supported them.
“Countless people — from world-renowned DNA experts, to former FBI agents, to everyday citizens committed to justice — have spoken about her innocence,” the family statement said. “We are thrilled with and grateful for today’s decision from the Supreme Court of Italy. And we are grateful beyond measure for all that so many of you have done for her.”
Kington is a special correspondent.
Staff writer Ryan Parker contributed to this report.