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 Meredith Kercher, a 21-year-old Briton 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 co-defendant Raffaele 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.
Presiding Judge Claudio Pratillo Hellmann said the jury would not emerge before 1800 GMT (2 p.m. EDT) at the earliest.
Kercher's mother, sister and a brother traveled to Perugia and were expected in to be in court for the verdict. They have expressed worry over the possibility of acquittal but told reporters as the jury deliberated that they hoped the jury would do the right thing.
"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 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's lawyer said it wants the original verdicts upheld.
"The lower court found the defendants guilty. The Kercher family's interest is to have the verdict confirmed," he said.
The highly anticipated verdict will be broadcast live. Hundreds of reporters and camera crews filled the underground, frescoed courtroom before Knox's address on Monday, while police outside cordoned off the entrance to the tribunal.
The trial has captivated audiences worldwide: Knox, the 24-year-old American, and Sollecito, a soft-spoken Italian, were convicted of murdering a fellow student 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.
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 have said Guede was the sole killer.
Knox said she had nothing more than a passing acquaintance with Guede, who played basketball in 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 was 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."
Knox and her family, present in Perugia, hope she will be set free after spending four years behind bars caught up in what they say is a monumental judicial mistake. Prosecutors, who have depicted Knox as a manipulative liar, are seeking to increase her sentence to life in prison.
The jury is made up of the presiding judge, a side judge and six jurors, five of them women, and they have several options as they go into deliberations. They can acquit both defendants and set them free. They can uphold the conviction, then confirm the sentence, reduce it or increase it. They can theoretically decide to split the fate of Knox and Sollecito, convicting one and acquitting the other.
The verdict doesn't have to be unanimous, only a majority is required. A verdict is expected late Monday, though in theory deliberations could continue into Tuesday.
Over the course of the appeals trial, the defendants' positions have significantly improved, mainly because a court-ordered independent review cast serious doubts over the main DNA evidence linking the two to the crime.
Prosecutors maintain that Knox's DNA was found on the handle of a kitchen knife believed to be the murder weapon, and that Kercher's DNA was found on the blade. They said Sollecito's DNA was on the clasp of Kercher's bra as part of a mix of evidence that also included the victim's genetic profile.
But the independent review - ordered at the request of the defense, which had always disputed those findings - reached a different conclusion.
The two experts found that police conducting the investigation had made glaring errors in evidence-collecting and that below-standard testing and possible contamination raised doubts over the attribution of DNA traces, both on the blade and on the bra clasp, which was collected from the crime scene 46 days after the murder.
The review was crucial in the case because no motive has emerged and witness testimony was contradictory. It was a huge boost for the defense's hope and a potentially fatal blow for the prosecution.
The prosecutors, however, refute the review and stand by their original conclusions.