Knox was emotional during her Friday interview with "GMA" anchor Robin Roberts.
"It really hit me like a train," she described. "I did not expect this to happen. I really expected so much better from the Italian justice system. They found me innocent once before."
Knox's voice quavered and she paused at times to maintain her composure, but the 26-year-old remained determined to fight the latest ruling in Florence that came down Thursday.
"I'm going to fight this to the very end. It's not right and it's not fair," she said.
Knox is currently living in the Seattle area. It was back in 2007 that she and her then-boyfriend Raffaele Sollecito were first found guilty of murdering Knox's English roommate Meredith Kercher.
After serving four years in an Italian prison, the conviction was thrown out in 2011 because of faulty evidence. However, Italy's supreme court overturned that ruling and an appeals court found Knox and Sollecito guilty again. The court sentenced Knox to 28 1/2 years in prison.
Knox, currently a student in Washington state, said she saw the verdict online via an Italian television station. She said she intended to wait until her lawyers gave her the news, but "I couldn't help myself."
"I couldn't believe what I was hearing. My whole family was there and I was listening and I'm the only one who knows Italian and I'm trying to listen and then tell them," she said.
She made it clear during the interview that she will not go back to Italy willingly and she insists she is innocent.
"No, this is wrong, and I'm going to do everything I can to prove it," she said. "This is an experience that I have to testify to, that really horrible things can happen and you have to stand up for yourself."
Roberts asked Knox if she was ready for extradition if Italy seeks to have her sent back.
"I'm not," Knox said firmly. "I will never go willingly back."
Knox said she has sent a letter to her lawyer addressed to Kercher's family.
"It's in the mail. Mainly I just want them to know that I really understand that this is incredibly difficult, that they've also been on this never ending thing and when the case has been messed up so much, like a verdict is no longer consolation for them," she said.
Meanwhile, Sollecito was also found guilty Thursday and sentenced to 25 years. He was apprehended early Friday at a hotel near the Italian border. He was not arrested, but police took his passport and ordered him not to leave the country.
Sollecito's lawyer told ABC News that he was not trying to flee the country, but rather going to his girlfriend's house in Treviso.
There is an appeal process with the latest ruling which could take another year. If it is upheld, then the Italian government would have to start the extradition process.
ABC News contributed to this report.