Italian Prosecutors alleged that Knox and her then boyfriend, Raffaele Sollecito, had killed Kercher in a sadistic, drug-fueled sex game gone wrong, but critics said there was a lack of conclusive evidence and accused the Italian authorities of facilitating a trial by media to make the couple look guilty.
Perugian local Rudy Guede was also arrested after his DNA was found on Meredith Kercher's body and in her bedroom, but no genetic trace of either Knox or Sollecito were found, the New York Times notes.
During the murder trial prosecutors painted Knox as a "sex-crazed femme fatale".
Knox and Sollecito spent four years in prison before being acquitted, but were convicted again in absentia in 2013 until another acquittal in 2015.
The international media circus around her trial inspired the 2016 Netflix documentary Amanda Knox.
Flying from her home in Seattle, Knox touched down in Milan early Thursday morning and headed straight for the northern city of Modena where she is due appear as a guest speaker at a panel discussion about wrongful convictions and miscarriages of justice organised by legal charity The Italy Innocence Project, CNN reports.
Meredith Kercher's family lawyer called Knox's return "inappropriate", The Telegraph reveals.
Knox is being accompanied by her mother and fiancé, Christopher Robinson, who said in a tweet: "Last time I was in Italy, I took a train to Florence, blew my money on a €100 bottle of Barolo which I drank by myself while writing a bad short story. This time with @amandaknox is going to be, shall we say…different.”
The trio were escorted through Milan airport by plainclothes police offers, People Magazine reports.
In an essay published to Medium's blog Your Content, My Life on Wednesday, Knox wrote: "I’m about to return to Italy for the first time since I was released from prison and fled the country in a high-speed chase, paparazzi literally ramming the back of my stepdad’s rental car."
In January, the European Court of Human Rights ordered the Italian government to pay just under $30,000 AUD to Amanda Knox for failing to provide legal assistance during her initial questioning after Meredith Kercher's body was discovered, according to the Associated Press.