The deliberations, underway for more than eight hours by 9pm CET, were expected to continue until a verdict was reached.
Lawyers involved in the case, however, said the six judges were likely to adjourn their discussions until Saturday morning if midnight passed without a consensus emerging.
The American and her Italian ex-boyfriend Raffaele Sollecito were convicted last year for a second time of taking part in the 2007 killing of Meredith Kercher, a British student with whom the then 20-year-old Knox shared a house in the university town of Perugia.
In final arguments to the Court of Cassation, Sollecito's lawyer said last year's ruling in Florence had been flawed, citing summing up mistakes on the number of stab wounds inflicted on Kercher's neck and a bloody footprint being described as that of a woman, when it belonged to a man.
"This is just a small taste of the mistakes that mean this verdict was a miscarriage of justice," Giulia Bongiorno told the court
She also pleaded for her client's case to be disassociated from that of his former girlfriend.
"Raffaele Sollecito is an innocent who finds himself involved in extraordinary events without realizing it," she said.
"He's like Forrest Gump. I ask you to annul the conviction," he said in a reference to the naive, slow-witted character in the 1994 film.
The six judges must now decide whether to confirm once and for all that the Italian judicial system regards the convictions as safe.
If they do, Sollecito could be taken straight back to jail while the absent Knox is likely to become the subject of a wrangle over whether she should be extradited from the United States back to Italy to join him behind bars.
The pair have already spent four years in jail - two on remand and two after their initial conviction for murder in 2009.
Alternatively, the judges could send the case back to the appeal stage, opening the door to one or both of the defendants being acquitted.
Bra strap and vibrator
The case has fascinated a global audience thanks to its youthful, photogenic cast, the gory and baffling nature of the crime itself and an endless supply of headline-friendly detail ranging from DNA traces found on the victim's bra strap to the 'rabbit' vibrator that Knox kept in a see-through toilet bag.
Prosecutors wrapped up their presentations on Wednesday by insisting that the Florence court called the case correctly.
That verdict came nine months after the former lovers were freed on appeal, allowing Knox to return home to Seattle, where she now works as a journalist and has reportedly become engaged to a childhood friend.
Her lawyers admit she is "very worried" about a possible extradition request, which legal experts say would stand a good chance of succeeding.
Harvard law professor Alan Dershowitz told AFP that Knox would likely seek to argue she had effectively been tried twice for the same crime, in breach of the double jeopardy principle.
"Legally she would have a weak case, but politically she would have a strong case. The real question is whether politics would prevail over the law."
Stabbed 47 times
Kercher, 21, died after being stabbed 47 times and having her throat slashed. Her half-naked body was found in a pool of blood in a back room of the house she shared with Knox.
Ivory Coast-born drifter Rudy Guede was jailed for Kercher's murder in 2008, but the judge in his trial ruled that he could not have acted alone.
Prosecutors believe Knox and Sollecito fatally slashed Kercher while Guede held her down. Her supporters see her as an innocent abroad who fell victim to a flawed judicial system.
Illustrating what the defence says was systemic police bungling in the case, Bongiorno said in court Friday that 35 people had tramped in and out of the crime scene, making critical DNA evidence inherently unreliable.
"The prosecution say Sollecito's DNA was on the bra strap but there was none on the floor. Did he manage to touch the bra without touching the floor?
"Not a single trace of Amanda Knox was found in the room. The only creature that does not leave DNA traces is a dragonfly."
Sollecito and Knox initially provided each other with alibis, saying they were sleeping together and smoking marijuana at another house when the murder took place. Sollecito has since said he could not be sure she was there for the whole time.