Brisbane Roar host Melbourne Victory in a top-of-the-table A-League clash on Saturday, while Adelaide and Sydney meet in a key battle.
Mike Mulvey's Roar side are nine points clear at the top and could seal the Premier's Plate with a win over Victory at Suncorp Stadium on Saturday.
But they will have to do so without star striker Besart Berisha, who has signed a deal with Victory for next season, after the Albanian was sent off in their 1-1 draw against Sydney.
That absence adds to depth that is already being stretched in Brisbane, who have the likes of Ivan Franjic, Jade North, Shane Stefanutto and James Donachie sidelined.
It gives Kevin Muscat's Victory a huge chance to consolidate second spot with an upset win.
Victory edged Yokohama F. Marinos 1-0 in the AFC Champions League on Tuesday but they have won just one of their previous 10 meetings against Roar.
Captain Mark Milligan and attacker Tom Rogic both came off the bench in the crucial Champions League win and should be fresh for the trip to Queensland.
On Friday, Adelaide United host Sydney FC at Coopers Stadium with both clinging onto their spots in the top six.
With four regular-season games remaining, Adelaide are two points clear of seventh-placed Newcastle Jets and one behind Sydney, who are fifth.
Josep Gombau's Adelaide side look the more likely of the two to finish in the top six and need to take three points at home.
For the loser, or if they draw, Newcastle or Wellington will be aiming to pounce when they meet at Hunter Stadium on Saturday.
Melbourne Heart can keep their slim chances of making the top six alive when they host Central Coast Mariners on Sunday.
On Wednesday, John van 't Schip signed a contract through until the end of the 2016/17 season with the Heart, who are second last and six points from sixth.
Western Sydney will fancy their chances of at least remaining third at the end of the round as they host bottom side Perth Glory on Sunday.