[2] Karnezis completed his move from Panathinaikos to Udinese Calcio, after the two clubs reached an agreement over the Greece international's transfer.

The 28-year-old keeper had been linked with a move to the Serie A side in recent weeks, with Panathinaikos manager Yannis Anastasiou keen to use income from the transfer to continue building his squad.

A fee of €750,000 had been quoted by the Greek press, with a further €2 million due to Panathinaikos if the player returned to Greece to play with another club in the future.

On 12 April, Karnezis was the key player in a 1–0 home victory against Barcelona, saving a shot from Cesc Fàbregas and a 20-yard free-kick from Lionel Messi.

[16] According to La Gazzetta dello Sport, discussions over a new agreement had begun and the 29-year-old goalkeeper was ready to put pen to paper, to extend his stay until 2020.

"Udinese Calcio announces the renewal with mutual satisfaction of the economic agreement in place with the goalkeeper Orestis Karnezis," read the statement.

"[18][19] In the opening game of the 2015–16 season against champions Juventus, Karnezis had a particularly strong second-half when Juve piled on the pressure, coming up with key saves and marshalling his backline to more effectively stop the Bianconeri forwards, helping his club to achieve a win.

[20] On 25 October 2015, he made key saves helping his club extend their unbeaten run in Serie A to four matches by edging to a 1–0 victory over Frosinone at the Stadio Friuli.

[22] On 8 November 2015, Karnezis kept his side level with two good pieces of goalkeeping, as Napoli continued to knock on the door, first when he dived low to keep out Gonzalo Higuaín's effort, before he smothered the ball at the feet of José Callejón minutes later, after Higuain had slipped the Spaniard through.

[23] On 20 December 2015, with his crucial saves, along with a late first half goal from his teammate Stipe Perica, who rifled a shot past the outstretched fingers of the ‘keeper to nestle inside the far post, and besides the fact that they finished the game with 10 players due to Molla Wague's expulsion, he helped his club to escape with a 1–0 away win against Torino.

[24] On 9 January 2016, despite his remarkable save one-on-one on Cristian Zaccardo, sticking out a trailing foot to deny the angled drive, his club suffered a surprise 2–1 away loss against Carpi in the Serie A.

[26] On 24 April, thanks to Karnezis, mUdinese managed to keep the score down to 3–1 against Inter as he made some fantastic saves to deny Geoffrey Kondogbia, Marcelo Brozović and Ivan Perišić, to keep his side afloat.

On 19 February 2017, in a frustrating defeat against Sassuolo, he reached 100 appearances in the jersey of Udinese in Serie A, in a game where the Greek international performed a desperate double save on Matteo Politano and the Federico Ricci follow-up.

[32][33] As a result of this possibility, since 14 May, Udinese's coach Luigi Delneri decided to start Simone Scuffet for the remaining matches of the season.

[34][35] On 5 November 2017, in a 3–2 away loss against Everton, the club lost first-choice keeper Heurelho Gomes, who was taken off with a nasty head gash shortly before Christian Kabasele's goal.

It proved to be the turning point, as Karnezis, on his Watford debut, was at fault for Everton's first when he came rushing out and Oumar Niasse darted past him and bundled the ball home.

[39] 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.

With his move to Lille, Karnezis makes history after becoming the first Greek footballer to have played in 4 of the 5 top European leagues, namely in the La Liga (Granada CF), Serie A (Udinese Calcio and S.S.C.

[43] Karnezis's good performances led Greece national football team coach Fernando Santos to call him for a friendly match on 29 February 2012 against Belgium, in which he made his international debut, playing the entire game.