Yves Bissouma was little more than a peripheral figure during his first season at the club, failing to win over Antonio Conte before Cristian Stellini and Ryan Mason's short-lived reigns.
However, the former Brighton & Hove Albion man excelled at the start of the 2023-24 campaign under Postecoglou, partnering up with Pape Sarr in an effective double pivot.
Bissouma has struggled to hit the same heights since returning from the Africa Cup of Nations, where he contracted malaria, but he has started Tottenham's last three games and was praised for his performance in their 4-2 loss to Liverpool.
The 27-year-old subsequently completed 75 minutes of Saturday's 2-1 comeback triumph over Burnley, and his substitution initially appeared to be tactical in nature, but Postecoglou has now confirmed that it was due to injury.
Bissouma, Richarlison ruled out for rest of campaign
Speaking to SPURSPLAY before Manchester City's visit to the Tottenham Hotspur Stadium on Tuesday night, the Australian coach confirmed that Bissouma had damaged his knee and would miss out on facing the Citizens.
In addition, the midfielder will also be unavailable for Spurs' final match of the season against Sheffield United on May 19, with Postecoglou saying: "Unfortunately, Biss picked up a knee injury in the last game and will miss the last two."
Bissouma is one of eight absentees for Postecoglou to work around on Tuesday, as Ben Davies (calf), Timo Werner (hamstring), Destiny Udogie (thigh), Manor Solomon (knee), Fraser Forster (foot) and Ryan Sessegnon (hamstring) are out for the season too.
Meanwhile, Postecoglou also confirmed that the calf issue Richarlison is nursing will also sideline him until next season, and the attacker will also miss this year's Copa America, having been left out of Brazil's squad for the continental championships.
"Not good, he'll miss the next two games. Nothing serious," Postecoglou said on Richarlison during his pre-game press conference. "Other than that everyone who was available is available."
What other selection dilemmas is Postecoglou facing?
The absences of Richarlison and Bissouma are easily solved, as Son Heung-min will simply start through the middle in place of the former, with Brennan Johnson bombing down the left flank.
Meanwhile, all of Rodrigo Bentancur, Giovani Lo Celso, Pierre-Emile Hojbjerg and Oliver Skipp are alternative options in the middle, although the latter was used as a left-back in the recent beating of Burnley.
Postecoglou took a punt on Skipp in that position after a series of sub-par performances from Emerson Royal, and Spurs fans have also been crying out for Micky van de Ven to be used as a makeshift full-back given his explosive pace.
The Lilywhites faithful briefly got their wish in the dying embers of the Burnley win, as Radu Dragusin beefed up the backline and Van de Ven switched over to the left, but pleas for Postecoglou to go with an identical tactic from the start on Tuesday may fall on deaf ears.
Skipp's lack of minutes could see him demoted amid the quick turnaround, while Postecoglou has already expressed a reluctance to start Van de Ven out wide due to his own injury issues, so a recall for Emerson may be the most realistic scenario for Tuesday's visit of the champions.