She returned to her studies at the University of Washington and kept her head down.
Italy's judicial system is based on a three-tier structure where no case is considered final until the highest court signs off on it.
When the decision to hold a retrial was made, Knox came out fighting.
"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," she said in a statement.
The court's decision was "painful," but the prosecution should be held accountable for the "many discrepancies in their work," she said -- not just for her own and former boyfriend Raffaele Sollecito's sake, but also for the family of Meredith Kercher.
Knox hit the media circuit a few months later to promote her memoirs, for which she was reportedly paid a $3.8 million advance.
She told CNN at the time that she hadn't decided whether to attend the retrial in Italy.
"I mean, I'm afraid to go back there. I don't want to go back into prison," she said. "I've been told that in Italy, people think it's arrogant of me to sit here in the United States and have a book come out and defend myself.
"First of all, I find that incredibly unfair, because I have the right to defend myself. And no one can ask me to just shut up because it's convenient. But at the same time, I want to prove to them that I care about what's going on."
When the retrial opened in September 2013, Knox was not present.
In December, her lawyer presented an emailed statement, written in Italian, to the retrial, in which Knox again protested her innocence.
"I must repeat to you. I'm innocent. I did not rape, I did not steal ... I did not kill Meredith," Knox said.
"'I was called a wolf in sheep's clothing, a rapist, a thief, psychotic ... Try to imagine your 20-year-old daughter being called all these things," she said. "I am not psychotic. I don't have a split personality."
Knox said the fact that she had stayed in Italy after Kercher's murder to help with the investigation demonstrated that she had not been involved in the killing.
The semi-naked body of the 21-year-old British student, her throat slashed, was found in November 2007 at the home she shared with Knox in Perugia, Italy.
The case has gripped the attention of the public in the United States, Italy and Britain ever since.
Part of the fascination lies in the competing narratives spun around Knox, and the many questions raised about her true character.
Dream turns to nightmare
Her younger sister, Deanna Knox, painted a picture of a wanderlust-driven young American who had hit the books hard and worked multiple jobs since high school so she could study abroad.
The chance to study at the University for Foreigners of Perugia was a dream come true for Amanda, Deanna Knox said.
And she fell instantly in love with the charming four-bedroom villa overlooking a small valley into which she moved after spotting a small ad on first arriving in town with her sister.
"She didn't need to see any other place, she didn't need to see any other listings, she was set," said Deanna Knox.
Kercher, a British exchange student, moved into the house shortly after Amanda Knox settled in. The two foreigners became fast friends, Knox's friends and family say, as they explored Perugia together.
Just weeks later, the home would be the scene of a grisly stabbing that would leave Kercher dead and Knox branded as her cold-blooded killer.
Prosecutors in Perugia said Knox directed Sollecito and another man infatuated with her, Rudy Guede, to hold Kercher down as Knox played with a knife before slashing Kercher's throat.
Both Sollecito and Knox were convicted in 2009 and sentenced to lengthy jail terms. Guede, a drifter originally from the Ivory Coast, was tried separately and is serving a 16-year sentence.
Then, after the evidence was reexamined, an appeals court quashed the two students' convictions in October 2011, citing a lack of evidence against them, and both were set free to return to a "normal" life.
Fast-forward 17 months and, in a case with as many twists and turns as a thriller, both faced the prospect of reliving the whole process again -- this time in a Florence appeals court.
Sollecito published a memoir in 2012, titled "Honor Bound: My Journey to Hell and Back with Amanda Knox."
In it, he writes that at times, he was uncomfortable with Knox's "bizarre behavior" after Kercher's death, which he says prosecutors used against both of them.
Some journalists have portrayed Knox as an overly trusting college student who some believe was railroaded by the Italian justice system. Other media paint her as a licentious, manipulative young American still trying to get away with murder, despite an alleged confession, which she quickly recanted, and a conviction, later quashed.
The fact that she was separately convicted of defaming Patrick Lumumba, a club owner whom she falsely accused of killing Kercher, feeds into the latter narrative. The Supreme Court did not order a retrial on this count.
But to Knox's friends and family, it's a no-brainer. They grimace at the description prosecutors painted of her as a resentful American so angry with Kercher that she exacted revenge during a twisted sexual misadventure.
Nothing in her past indicated she had the desire or capacity to kill anyone, let alone a friend, they say. One friend told CNN she was the kind of person who would pick up a spider and take it outside rather than kill it.
More than anything, they say, her life had been all about immersing herself in new experiences and creating opportunities to travel abroad.
Growing up in Seattle, Washington, Knox was an easy daughter from the start, said Edda Mellas, her mother.
She was a child who never had to be told to do her homework or go to bed on time. She maintained a balance between a life indoors, where she studied regularly and read for pleasure, and a passion for outdoor activities and sports, in particular gymnastics and soccer.
Knox's desire to study foreign languages and experience different cultures also became apparent early on, Mellas said.
She took Latin in middle school and began expressing a desire to travel abroad. Even though her parents told her they couldn't afford a private high school, she applied on her own and was accepted with a substantial scholarship.
She learned Japanese in high school and spent time in Japan as part of her studies, her mother said.
"She loved learning languages. She thought about being an interpreter. She really wanted to be a writer and I said, 'Maybe you need to get a day job while you're trying to make money being a writer.' And then she thought about being an interpreter. Languages were definitely her kind of gift."
Knox eventually set her mind on studying abroad in college. She rejected soccer scholarships from several schools because she knew she would have to commit to the sports program.
Instead, she set her sights on a long shot: the highly competitive University of Washington. She got in and made a positive first impression on practically everyone she met, says friend Andrew Seliber, who testified at her trial as a character witness.
"I think it was her just open personality to, you know, see the good things in people and have always a positive attitude about everybody and everything in the world. And it was really refreshing coming to school and meeting people like that, especially like her, who were, you know, so willing to see everybody's perspectives about, you know, anything."
She considered Germany, Austria and Scotland, her mother says, before deciding on Italy, a place she'd never been and where the people spoke a language she hadn't studied.
"She wanted to try something different," Mellas says. "Once she decided on Italy, she thought about going to the really typical places: Florence or Rome. But she really thought that to her seemed more touristy. And she wanted just everyday, small-town, regular Italians and not where there would be hundreds of English-speaking people. She wanted to immerse herself in a smaller town, and she looked around and Perugia had a program."
Finally, the time arrived for her to begin her adventure in August 2007.
She and her sister went to Europe to visit relatives before catching a train to Perugia. From the start, it was an adventure, her sister says.
"The city was really beautiful. You could really tell on Amanda's face and how she was acting that she was instantly in love," Deanna said.
After school began, Knox sent enthusiastic e-mails to her family nearly every day. She described attending a chocolate festival and a book fair with Kercher.
A few weeks into her stay, she wrote in various e-mails that she had met a handsome computer engineering student who looked like Harry Potter at a classical music concert.
Knox had been a "late bloomer" in terms of dating, so news that she had met Raffaele Sollecito made her sister happy.
"She was just infatuated with the whole idea of him. First of all, he was a foreign guy, he was sweet, he was really kind, he was smart ... He was exactly my sister's type." Deanna Knox said. "It was pretty exciting. I wanted to learn more about him, and it just happened that they were only dating for two weeks before everything happened. I wish -- I really wish that they could've gotten to know each other a lot better."
Sollecito, in an epilogue to his memoir, said he had been to visit Knox in Seattle after their acquittal but was nervous to see her, wondering if after going through so much, "perhaps we owed it to each other to live our lives and leave each other in peace."
In October 2013, he told CNN that his life was "now a hell," but that it was the fault of prosecutors and investigators -- and not Knox.
Sollecito, who faces a 25-year jail sentence if the court upholds the conviction,
said he would be in court on Wednesday to face the judge. He told Italy's Quarto Grado crime program: "I've been living this for eight years. Not appearing in court would be like hiding in the corner during a tsunami, it will take you away anyway."
As for Knox, asked in January 2014 by Italian daily La Repubblica what she would do if the retrial found her guilty, she replied. "I will become ... a fugitive."
However, what would happen to her next is uncertain. And depending on the decisions made by Italy and the U.S. on her fate, relations between the two nations also hang in the balance.