She boarded a plane in Italy and flew to London, where she caught a connecting flight to the United States. Her flight touched down at Seattle-Tacoma International Airport just after 5:15 p.m. PT.
Knox spoke to members of the media shortly after stepping off the plane.
"I'm really overwhelmed right now," Knox said. "I was looking down from the airplane and it seemed like everything wasn't real.
"Thank you to everyone who has believed in me, who has defended me, who has supported my family. My family is the most important thing to me right now and I just want to go and be with them. Thank you for being there for me."
On Monday, an Italian appeals court overturned Knox's conviction of sexually assaulting and brutally killing her British roommate, Meredith Kercher, in 2007.
The prosecutor said he would appeal the decision releasing Knox, 24, and her Italian co-defendant and one-time boyfriend, Raffaele Sollecito.
Kercher's family was stunned by the verdict and continued to search for answers. They said they're shocked and bewildered by the reversal of the 2009 decision.
Lyle Kercher, the victim's brother, said the family has been left to wonder who is guilty. A third man has been convicted in the brutal slaying. However, his trial concluded he did not act alone.
Citing legal experts, ABC News reports Knox's parents likely spent more than $1 million on her defense.
Monday's verdict was controversial. Hundreds of mostly university-age young people jeered and yelled in the piazza outside the courtroom in Perugia, while Knox's supporters in her hometown of Seattle hugged and shouted in joy.
In a letter to a foundation aimed at promoting ties between Italy and the U.S., Knox thanked Italians who have supported her throughout her legal ordeal.
"Those who wrote, those who defended me, those who were close, those who prayed for me, I love you," she wrote.
In Seattle, there was a large security presence at Sea-Tac, as well as media from around the world, in anticipation of Knox's arrival.
"It's been a very long four years but we couldn't have made it without all you people who supported us," said Knox's father, Curt.
Now that their nightmare is finally over, the Knox family is asking the public and the media for privacy so they can reunite with their daughter after spending the last four years apart.
View photos of Amanda Knox reacting after an Italian appeals court overturned her murder conviction.
The Associated Press contributed to this report.