Four years later, after she was acquitted by an Italian appeals 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.
But her effort to keep a low profile was upended Tuesday, when Italy's highest criminal court overturned her acquittal and ordered a new trial.
Knox said it was "painful" news after the trial showed the prosecution case was unfounded and unfair.
"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," she said in a prepared statement.
Italian law cannot compel Knox to return for the new trial. And family spokesman David Marriott said it's "very doubtful" that Knox will make the trip.
Instead, she will continue to attend the University of Washington, where she is a junior, he said. No public appearances were immediately planned.
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.
"She's living the life of a normal college student," said Candace Dempsey, a Seattle journalist and author of "Murder in Italy," a book about Knox. "I think we're seeing who she really is - that she's not the drug-crazed, sex-hungry American girl that the prosecutors have fantasized."
Dempsey said she was stunned by the decision of the Italian high court.
"Of course it's an absolute nightmare for her and her family," said Dempsey, who has talked with Knox since she returned to Seattle in 2011.
Amanda'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."
Knox grew up in West Seattle, a tight-knit neighborhood known for a slower pace of life than other parts of the city.
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 activities 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.
"Having this renewed spotlight must be particularly unsettling," said Tom Wright, whose daughter attended high school with Knox. With parents and other people, Wright helped start the Friends of Amanda Knox group.
"Our group pretty much disbanded when she came home and if necessary we'll reconstitute ourselves and advocate for her again," he said. "Everybody who cares about this young lady continues to believe in her innocence, and believes the court will make the right decision."
Mark Waterbury, a materials scientist interested in forensic techniques, has been a Knox supporter and wrote the book "The Monster of Perugia: The Framing of Amanda Knox."
"It just amazes me that the system drags on for such a long period of time, when the case would have been thrown out in the United States long ago," he said. "It leaves the public without a positive resolution, so it leaves a cloud hanging over her head.
"It's as if the real goal all along is to destroy Amanda, and not to seek justice in any way," he said.
Knox's 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 also planned to talk with ABC News celebrity interviewer 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.
If Knox is convicted and Italy requests her extradition, it would be up to U.S. authorities to decide whether they will send Knox to Italy.
She previously spent four years in an Italian prison after an initial conviction in the case. She was later acquitted by the appeals court.