Prosecutor Alessandro Crini said Italy's highest court had "razed to the ground" the Perugia appellate court's 2011 decision to throw out the guilty verdicts.
The high court ordered a fresh appeals trial, this time in Florence, saying the earlier appeals decision was full of contradictions.
Knox and Sollecito were convicted in 2009 of killing Meredith Kercher, Knox's 21-year-old British roommate, who was found with her throat slit in her bedroom in 2007.
They were sentenced to 26 years and 25 years in jail, respectively. After being freed in 2011, Knox returned to the United States and has not returned to Italy for the current trial.
Knox and Sollecito denied any involvement in the killing, saying they weren't in the apartment at the time and had no motive.
A third defendant, Ivory Coast-born Rudy Guede, was convicted in a separate trial of sexually assaulting and stabbing Kercher. His 16-year sentence, reduced in appeal from 30 years, was upheld by Italy's highest court in 2010. Prosecutors have argued that the murder was carried out by more than one person.
Crini argued that the earlier appellate court had "pulverized the elements," separating pieces of evidence that needed to be seen together to get a full picture of the crime.
Crini said Knox and Sollecito made efforts to deflect suspicion. He alleged they staged a break-in at the apartment to make it appear the killer was an outsider; he alleged Knox cleaned up the apartment in an effort to remove any evidence linking her or Sollecito to the crime, and that she falsely accused another man of the crime.
The defense has argued that the robbery was not staged and that it would be impossible to selectively remove incriminating evidence.
After more than six hours of arguments, the hearing was continued until Wednesday when the hearing turns to possibly significant new DNA evidence, the main new element of the second appeals trial. The prosecutor will also make his sentencing demands.
The Florence court ordered experts to test the tiny trace of DNA not examined in the previous trials, one of the appellate trial flaws emphasized by the Cassation Court in vacating the acquittals. An expert testified that the trace on the purported murder weapon was consistent with Knox's DNA and not Kercher's.
Knox's DNA had previously been identified on the knife, and her lawyers see the new evidence as confirmation that Knox had used the knife - found in a kitchen drawer at Sollecito's apartment - for cooking.
The first trial had identified another trace of DNA on the tip of the knife as belonging to Kercher, but that evidence, which was key in securing the convictions, was discredited by expert testimony to the Perugia appeals court.
Knox's lawyer, Luciano Ghirga, said there was nothing new so far in the prosecutor's summations. "No new arguments were made, but it was a good presentation," Ghirga said.
Sollecito was in the Florence appellate court for a second time Monday, listening intently as Crini claimed that his alibi that he was working at his computer at the time of the murder was false.
"After all of this time," Sollecito told reporters outside court, "I just continue to confront a situation of repeated accusations that have no foundation in reality or likelihood."
A verdict had been expected on Jan. 10, but may be delayed as the closing arguments have run longer than anticipated by the court.