Wayne Bennett will need to call on all the depth at his disposal as South Sydney continue to pick up injuries in key positions.
While the Rabbitohs were able to claim a dramatic six-point win over the Roosters on Friday night, the win came at a cost, with scans revealing hamstring strains of varying grades for Cody Walker, Jamie Humphreys and Mikaele Ravalawa.
The club on Monday confirmed Walker would be out of action for 2-3 weeks, Humphreys for 4-5 weeks and Ravalawa 6-8 weeks.
MORE: NRL round 6 team lists
That trio joins a host of their teammates on the sidelines, with Cameron Murray, Campbell Graham, Alex Johnston, Tyrone Munro and Euan Aitken among the injured brigade at the club.
Munro and Aitken are believed to be nearing returns but it remains to be seen whether they'll be available to play the Cowboys at Perth's Optus Stadium on Saturday.
As the injuries mounted on Friday, several players were forced into unfamiliar positions, including Tallis Duncan and Jai Arrow in the centres.
With first-choice halves pairing Walker and Humphreys out, new recruit Lewis Dodd could have been given a chance to make his NRL debut at halfback, although a suspension due to a crusher tackle in reserve grade has also ruled the Englishman out.
That leaves Jayden Sullivan, who filled in at halfback as the injuries mounted against the Roosters, without an experienced, natural halves partner.
Latrell Mitchell is most likely to be shifted from centre to five-eighth for this weekend - his creative strengths were on full display as he threw the pass which ultimately earned his side the match-winning try in round five.
Mitchell missed the opening month of a season with a hamstring injury of his own but that opened the door for the rising Jye Gray to have an extended run at fullback in what has turned out to be the brightest of silver linings for the club.
Bennett will be hoping the latest batch of replacements can prove similarly effective in first grade.
One left field name that has been mentioned is Josh Schuster.
After a year out of the game, Schuster joined Souths on a cut-price, one-year deal.
The former Manly player, who is still just 23, was touted as a future star but his career stalled on the Northern Beaches amid injury and fitness concerns.
A calf problem has kept him out of action so far in 2025 but Schuster has reportedly been seen training with the Bunnies' NRL squad this week.
While he's likely to make his return via NSW Cup, he could be an X-factor option in the coming weeks if Souths' bad luck on the injury front continues.
South Sydney predicted team for round 6 vs. Cowboys:
1. Jye Gray
2. Isaiah Tass
3. Latrell Mitchell
4. Jack Wighton
5. Tyrone Munro
6. Jayden Sullivan
7. Lewis Dodd
8. Sean Keppie
9. Peter Mamouzelos
10. Tevita Tatola
11. Keaon Koloamatangi
12. Jai Arrow
13. Lachlan Hubner
14. Siliva Havili
15. Tallis Duncan
16. Davvy Moale
17. Liam Le Blanc