The supreme court ruling comes over a year after Knox and her former boyfriend, Raffaele Sollecito, were sentenced to 28 years and 25 years, respectively, for the 2007 murder by a Florence court.
“It’s very difficult to know what the outcome on Wednesday will be, but I hope the court confirms the verdict so that the case can finally be over,” Francesco Maresca, a lawyer for the Kercher family, told The Local.
“If the verdict is upheld, then I will ask the government to call for Knox’s extradition.”
Sollecito, who is in Italy, would be immediately arrested if the court confirms the conviction.
But there is a possibility that the supreme court could order a retrial, Maresca added.
US authorities may try to argue that Knox has been a victim of double jeopardy, but the extradition treaty acknowledges that there is no limit on the number of times cases can be appealed under the Italian legal system.
The pair have already served four years for the murder and were acquitted in 2011, but the supreme court overturned that ruling in 2013, sending the case back for re-trial.
When Knox, who in February got engaged to a 27-year-old musician, returned to the US after the 2011 acquittal, she vowed never to return to Italy.
The Florence court said there was DNA proof that three people were at the murder scene: Knox, Sollecito and a third person, Ivory Coast-born drifter Rudy Guede, who is the only person still in prison for the crime.
Both Sollecito and Knox have argued the crime scene was contaminated and any DNA collected was therefore not viable.
Preparing for the high court ruling last summer, Sollecito’s lawyer, Giulia Bongiorno, unveiled a new defence strategy in which she cast doubt on Knox’s alibi.
Kercher, an exchange student from London, was found half-naked in a pool of blood with multiple stab wounds on November 2nd 2007 in the house she shared with Knox in the university town of Perugia in central Italy.
Public opinion in the US has long felt the case against Knox was flawed and that Italian detectives made mistakes - such as using dirty gloves to collect evidence - which mean the case should have been thrown out years ago.
Difficult to resist extradition
The US might say returning Knox to Italy's notoriously overcrowded prisons would be a breach of her human rights, and offer to see her serve time back home. A pregnancy could also make it less likely for the US to hand her over.
Harvard law professor Alan Dershowitz said he believes "she will be extradited if it's (the guilty verdict) upheld."
"The Italian legal system, though I don't love it, is a legitimate legal system and we have a treaty with Italy so I don't see how we would resist," he said.