Manolas was a key figure for AEK Athens in the 2010–11 season, playing impressive performances in the Superleague Greece but also in the 2010–11 UEFA Europa League, which drew interest from many European teams such as Genoa, Udinese, Getafe and Schalke 04.

His impressive performances convinced then AEK Athens coach Manolo Jiménez and earned him a spot in the starting line-up, forcing Real Madrid loanee David Mateos to the substitutes' bench.

[10] Shortly after signing the contract, Manolas stated to the press, "I am extremely happy that I am going to continue playing for the team of my heart and it is an honour to wear the AEK Jersey for the next three years with my childhood club.

During the January transfer period, the English Premier League's Everton showed sincere interest in the young centre back, with the team's then-manager David Moyes stating, "Manolas has huge talent and is a player for the future.

"I am very happy that I'm at Olympiacos and I can't wait to play with the red and white shirt in front of a full Karaiskaki and our fans," Manolas said.

[6][18] Reports in Greece suggested that English clubs Tottenham Hotspur, Sunderland and Fulham were all keeping an eye on Manolas ahead of the January transfer window.

[citation needed] According to Gazzetta.gr, Manolas had captured the attention of Premier League scouts since moving to Olympiacos on a free transfer from AEK the previous summer.

[21] He scored his second goal in the Champions League in a 2–1 away loss against Paris Saint-Germain,[22] though nonetheless the squad secured a spot in the round of 16—the first time the club had reached the stage since 2009–10—in matchup against Manchester United.

"[31] Manolas enjoyed an excellent first season in Serie A, cementing his place at the heart of manager Rudi Garcia's defence as his side finished second in the league table.

According to Tuttomercatoweb, Chelsea manager José Mourinho attempted to bring the Greek international to Stamford Bridge the previous season, and will try again in the New Year, with Arsenal and Tottenham Hotspur continuing their interest.

[37] On 5 December, in a dramatic 1–1 away draw against Torino in domestic league action, Manolas brought down Andrea Belotti inside the area, whereupon Maxi López coolly converted the subsequent 94th-minute penalty kick.

[38][39] On 11 December, towards the end of a Champions League match against Belarusians BATE Borisov, Manolas engaged in a quarrel with teammate Miralem Pjanić for mishandling a ball possession.

[40][41] On 17 February 2016, in a 1st leg UEFA Champions League game for the last 16, he was the indisputable leader of the defence, despite the 2–0 home loss from the Spanish giants Real Madrid.

On 31 October, he broke his nose in AS Roma's 0–0 away draw against Empoli, in a game where the Greek defender simply covered every possible hole, thus missing Europa League clash against FK Austria Wien and Serie A match with Bologna at the Olimpico, the Giallorossi said.

[51] On 4 December 2016, in one of the most spectacular Roman derbies in history, Manolas showed the usual ability both in anticipating and blocking his opponents, giving Balde Diao Keita and Ciro Immobile a very difficult afternoon.

[52] On 13 December 2016, Roma's center-back trio had an amazing performance, especially Manolas and Federico Fazio who combined 15 clearances, 11 interceptions and won 12 duels.

Manolas was forced off in the latter stages at Juventus Stadium, and he will now miss Roma's match against Chievo, the defender having already been struck down with a broken nose and muscle strain this season.

To avoid the worst, only the provisional intervention of teammates, along with Luciano Spalletti's decision to send them to the dressing room without even finishing the training, helped to lower the tension.

[66][67] On 4 April 2018, in a frustrating 4–1 away loss for 2017–18 Champions League quarter finals 1st leg to FC Barcelona, Manolas scored Roma's second own-goal after a clearance that in turn hit the right post, Samuel Umtiti and the Greek defender.

[71] On 27 August 2018, Manolas scored against Atalanta, as he tapped in Javier Pastore's chipped free kick at the far post, helping Roma complete a comeback from 3–1 down to 3–3 at the Stadio Olimpico.

[72][73] On 7 November, Manolas scored with a glancing header from very close range, placing the ball high and in the centre of the goal, from an assist by Lorenzo Pellegrini with a cross following a corner, helping his club to a vital 2–1 away win against CSKA Moscow in the group stage of the UEFA Champions League.

Reports from the Italian media later confirmed that the 27-year-old had strained a muscle, and would miss around three weeks of action, meaning that he would not be expected to participate in his nation's UEFA Euro 2020 qualifying matches against Liechtenstein and Bosnia and Herzegovina.

[82][83] On 28 September, Manolas scored his second goal of the season with a header after Nikola Maksimović's corner, helping his club seal a 2–1 home win game against Brescia.

[85] On 29 February 2020, Manolas connected with Lorenzo Insigne's free-kick from the right wing, thumping a header into the net to give Napoli the lead in a 2–1 home win game against Torino.

[90] In August 2021, it was reported that Olympiacos had started negotiations with Napoli for the purchase of Manolas, with the player telling the club that he desired a return to Greece.

Leading up to the 2014 World Cup, Manolas' strong 2013–14 season with Olympiacos earned him a spot in manager Fernando Santos' final 23-man squad for the tournament.

[102] It was in Brazil where the centre-back really caught the attention of the watching world, with a string of imperious displays that carried Greece into the knockout stages of the tournament for the first time in its history.

[103] On 9 June 2017, Manolas and his Roma teammate Edin Dzeko came to blows during an ugly brawl in World Cup qualifier game between Bosnia-Herzegovina and Greece.

[104][105] On 12 September 2018, Manolas netted his first goal with Greece, leaping over his marker to head a free kick through the goalkeeper's hands in a 2–1 away loss against Hungary for the Nations League.

Although he is primarily known as a stopper, he is also a solid passer; indeed, few players better combine the virtues of an old-fashioned centre-half with the modern need to build play from the back.