Amanda Knox – who is in the US – and her Italian ex-boyfriend Raffaele Sollecito had pleaded not guilty.
She was sentenced to 28 years and six months in jail, while Raffaele Sollecito received 25 years.
The latest verdict overturns the pair’s successful 2011 appeal, which freed them after four years in jail.
Meredith Kercher was stabbed to death in the flat she shared in Perugia with Knox.
The judges ordered that damages should be paid by the pair to the family of Meredith Kercher.
Meredith Kercher’s brother Lyle and sister Stephanie were present when the verdict was read out.
Raffaele Sollecito was ordered to surrender his passport. Extradition proceedings against Amanda Knox, who refused to return to Italy for the case, may now begin.
Thursday’s fresh appeal hearing in Florence was ordered by Italy’s highest court, the supreme court in Rome.
It had found that the 2011 appeal – which acquitted the pair – was flawed.
The court in Florence heard from Amanda Knox’s defense team in the morning, before the two judges and eight jurors retired to deliberate on a verdict.
Summing up, Amanda Knox’s lawyer, Carlo Dalla Vedova, told the court her innocence was “rock-solid and it allows us to await the verdict with serenity”.
The Supreme Court overturned their acquittals last March after an appeal by prosecutors, who argued that important DNA evidence had been disregarded.
Meredith Kercher, from Coulsdon in south London and 21 at the time, was found with her throat cut in a flat she shared with Amanda Knox in the college city of Perugia, in the central region of Umbria.
Rudy Guede from the Ivory Coast was convicted of her murder at an earlier trial and sentenced to 16 years in prison.
Prosecutors sought to prove Meredith Kercher had died in a sex game involving Amanda Knox and Raffaele Sollecito that had gone wrong.
They have since alleged that the murder resulted from a heated argument over cleanliness in the Perugia apartment.
Arrested days after the murder and detained in prison, Amanda Knox and Raffaele Sollecito were tried and convicted in November 2009.
In 2011, an eight-member jury cleared Amanda Knox and Raffaele Sollecito of Meredith Kercher’s murder after doubts were raised over procedures used to gather DNA evidence.
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