The high level of media interest also contributed to the failings of the case, the high court said.
"The international spotlight on the case in fact resulted in the investigation undergoing a sudden acceleration, that, in the frantic search for one or more guilty parties to consign to international public opinion, certainly didn't help the search for substantial truth," the judges wrote.
It is standard practice in Italy for the Court of Cassation to release a formal written explanation for a verdict months afterwards.
Knox was definitively cleared in March over the 2007 murder of Miss Kercher, a 21-year-old Leeds University student from Surrey, after nearly a decade of courtroom saga. She and Sollecito each served four years in prison after being convicted of the crime in 2009. They were released and then retried.
A man from Ivory Coast, Rudy Hermann Guede, was convicted in separate proceedings and is serving a 16-year sentence.
The Cassation panel of five judges essentially concluded that while there were indications Guede could have had accomplices, nothing in the prosecutors' case proved that either Knox or Sollecito were involved in the murder.
It also wrote that the lower court ignored expert testimony that "clearly demonstrated possible contamination" of evidence and misinterpreted findings about the knife allegedly used to slit Kercher's throat, in what prosecutors had described as a sexual assault.
The court's explanation for the verdict is tantamount to a "great censure, a note of solemn censure of all the investigators," Carlo Dalla Vedova, Knox's defence lawyer, told The Associated Press.