She hasn't been back to the country since she and her ex-boyfriend, Raffaele Sollecito, were acquitted of killing Meredith Kercher, Knox's then-roommate while she was studying abroad, in 2007.
The case made Knox a household name and led to books and even a TV movie adaptation about the murder.
Knox was convicted of the murder and spent years imprisoned before she was freed following an appeal. Sollecito's conviction was also overturned. A third man, Rudy Guede, was ultimately convicted of Kercher’s murder and he remains behind bars.
After being freed, Knox had vowed never to return to the country, but now she's agreed to speak at a criminal justice festival about wrongful convictions.
She admitted in an Instagram post that she was nervous to go back, however.
"3 Days till I return to Italy for the first time since leaving prison," she wrote, captioning a picture of her dangling off a cliff in Washington state, where she now lives. "Feeling frayed, so I made my own inspirational workplace poster. 'Hang in there!' Just imagine I'm a kitten."
Could Knox face repercussions when she returns, though? Attorney Anne Bremner, the Knox family's former spokeswoman, said she will in all likelihood be fine.
"I can't imagine in any scenario that she would be prosecuted again for anything," Bremner told Inside Edition. "Legally, there's just nothing they could do now even though they don't have double jeopardy. Her case is done."
She added: "I think enough time has passed and she's very wedded to the focus and conviction to help other people with what she's gone through."
Knox has tried to live a low-key life following her release, living in west Seattle with her fiance, Christopher Robinson, who's accompanying her on the Italy trip.
"Here we go... Wish us, 'Buon viaggio!'" she captioned a pic Tuesday of her and Robinson as they headed off.