Four years later, after she was acquitted by an Italian court of killing her roommate, she returned a famous woman, greeted at the airport by media from around the globe.
Since then, the 25-year-old Knox has tried to return to the life she knew before the murder case.
However, the attempt was upended Tuesday, when Italy's highest criminal court overturned her acquittal and ordered a new trial.
"No matter what happens, my family and I will face this continuing legal battle as we always have, confident in the truth and with our heads held high in the face of wrongful accusations and unreasonable adversity," Knox said in a statement Tuesday.
Family spokesman David Marriott said it's "very doubtful" that Knox will travel to Italy for the new trial and instead will continue to attend the University of Washington, where she is a junior.
No public appearances were immediately planned, he said.
Since returning home, Knox has largely avoided the public spotlight and is mostly left alone in her Pacific Northwest hometown known for its rain, stunning water and mountain views, and polite but restrained residents.
"My family's the most important thing to me," she said tearfully at a packed airport news conference shortly after she was released from an Italian prison. "I just want to go and be with them."
Amanda Knox's father, Curt Knox, cited the statement by his daughter and declined further comment on Tuesday.
Asked how she's faring, he said, "I think it will be portrayed in the statement."
Amanda Knox grew up in West Seattle, a tight-knit neighborhood known for a slower pace of life than other parts of the city, where many people grow up and never leave.
She graduated from the private Explorer West Middle School in 2001 then earned a scholarship to Seattle Preparatory School.
At the University of Washington, Knox studied writing and foreign languages and enjoyed rock climbing, hiking, camping and other outdoor activity offered in the Northwest.
Since her return, she has occasionally been seen with her boyfriend, a musician. But the local media largely leaves her alone, as do most residents.
Her self-imposed silence could be coming to an end with the scheduled release late next month of her memoir. Her book deal with HarperCollins was reportedly worth $4 million.
Knox planned to talk with ABC News anchor Diane Sawyer in a prime-time special to be broadcast April 30 to promote the book "Waiting to be Heard."
ABC News spokesman David Ford said Tuesday the interview was moving forward as planned.