On 23 October 2016, Manolas reached 100 appearances with the jersey of Roma, in a 4–1 home win Serie A game against Palermo. 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. 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. 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' impact surpassed just defensive duties as he assisted for Radja Nainggolan's 1–0 winner against A.C. Milan. On 18 December 2016, Manolas according to doctors' report, will be out for around two weeks after picking up another injury in Roma's 1–0 defeat to Juventus. 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. On 8 January 2017, he returned to the squad playing as a late substitute in a 1–0 away win against Genoa. On 25 May 2017, a week before the end of the season, Manolas and Diego Perotti came a step away from putting their hands on them during training. 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.