On 5 July 2018, Napoli announced the signing of Karnezis from Udinese on a three-season contract, for an estimated fee of €2.5 million. The 32-year old would compete with Alex Meret, a young promising Italian goalie, for the starting place at Stadio San Paolo. On 17 August 2018, after Karnezis' mediocre appearances in the preparation matches, in the place of Meret who seriously injured a month ago, the administration of the club decided to acquire David Ospina in a season-long contract from Arsenal, who took over as the leading goalie for the beginning of the 2018–19 season. On 18 August 2018, despite the odds, he made his official debut with the club as a starter, in a 2–1 away win against S.S. Lazio.