The court, after 12 hours of deliberations, also found Knox's former Italian boyfriend Raffaele Sollecito guilty for killing Meredith Kercher in the university town of Perugia and sentenced him to 25 years.
"The court...determines a sentence of 28 years and six months for Amanda Knox," said the presiding judge, Alessandro Nencini.
Knox was following the proceedings from her hometown of Seattle in the United States, where she has lived since a previous acquittal in 2011.
"It was a real blow," said her lawyer, Luciano Ghirga.
Experts say it is extremely unlikely Knox could be extradited even if the sentence is upheld by the supreme court, although her freedom of movement outside the United States could be severely curtailed.
Sollecito was also not in court for the verdict, although he attended a hearing earlier on Thursday.
Nencini ordered that Sollecito's passport be withdrawn to stop him leaving the country.
"This conviction was based on nothing. It's absurd. Raffaele Sollecito is innocent," Sollecito's lawyer, Luca Maori, told reporters after the verdict.
Maori said he would appeal to the supreme court.
Leeds University exchange student Kercher was found dead in the house she shared with Knox on November 2nd 2007 in mediaeval Perugia in central Italy.
Explaining her decision not to return to Italy, Knox, 26, told the New York Times: "I would be putting myself in the hands of people who very clearly want me in prison for something that I didn't do."
Kercher's family were also in Italy for the ruling.
Speaking ahead of the verdict, her 34-year-old brother Lyle said: "We are not going to get closure today, so there won't be any celebration on our part, but it's hopefully a step towards reaching a conclusion."
"To lose someone you love so dearly is hard enough, especially in the way she died, but that has been compounded by the fact that it has gone on for six years and three months."
Lyle and Stephanie Kercher, siblings of victim Meredith Kercher, in court with Pierluigi Puglia from the British Embassy in Rome. Screenshot: Corriere TV
Knox, Sollecito and a third person, drug dealer Rudy Guede, were initially convicted for the crime, which prosecutors said was the result of a sex game turned violent due to tensions between Kercher and Knox.
Guede is now the only one of the three still in prison after exhausting his appeals but investigators say that multiple stab wounds on the body from two different knives indicate he could not have acted alone.
Knox and Sollecito have always protested their innocence and Guede has changed his story several times but maintains he did not commit the murder although he was in the house when it happened.
Prosecutors had asked for Knox to be given a 30-year sentence and Sollecito 26 years, saying the punishment should be harsher for her because she initially accused someone else of the crime, bar owner Patrick Lumumba.
'I am not a monster'
Knox says the accusation of Lumumba, as well as her since retracted memory of hearing Kercher's screams, were due to intimidating police interrogation tactics.
Knox now says she was at Sollecito's house that night. The two 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.
Thursday's verdict will still not be the final word in the long-running case since the defence has indicated it will appeal to the supreme court again.
Knox explained her absence in an email to the court in which she told jurors: "I am not a monster".