Knights co-captain Hannah Southwell will miss the rest of the NRLW season and the Rugby League World Cup after scans confirmed she had ruptured her ACL.
Southwell suffered the injury to her right knee in Newcastle's 32-14 win over Brisbane in the season opener on Sunday night.
The 23-year-old lock slipped while running towards the defensive line in the 17th minute.
She rose gingerly on the field and managed to play on until half-time, but did not return after the break.
Knights coach Ron Griffiths was hoping for the best after the game, but scans revealed the club's worst fears on Tuesday.
One of the game's premier forwards, Southwell now faces surgery and six months to a year of rehabilitation.
She will miss not only the rest of Newcastle's campaign, but the Rugby League World Cup in England in October.
It is a crushing blow for the Cameron Park product, who was playing her first game for Newcastle on Sunday and with 17-year-old sister, Jesse, for the first time in the NRLW.
Jesse starred on debut as Newcastle's halfback, scoring the opening try and making a 60-metre break that led to another.
Newcastle were impressive first-up and have already improved on their winless inaugural campaign from earlier this year. But the loss of Southwell could prove a blow to how well they fare this season.
Simone Karpani, who made an impact off the interchange bench against Brisbane, was named on Tuesday to replace Southwell at lock for the side's clash with the Gold Coast on Sunday night. The game at Cbus Super Stadium follows the NRL match between the Knights and Titans that afternoon.
Twenty-year-old Queenslander Makenzie Weale comes onto the bench for the Knights. The West Arana Panthers junior will make be making her NRLW debut.
Knights (vs Titans)
1 Tamika Upton
2 Kiana Takairangi
3 Shanice Parker
4 Bobbi Law
5 Autumn-Rain Stephens-Daly
6 Kirra Dibb
7 Jesse Southwell
8 Caitlan Johnston
9 Olivia Higgins
10 Millie Boyle (c)
11 Romy Teitzel
12 Yasmin Clydsdale
13 Simone Karpani
Interchange
14 Emma Manzelmann
15 Tayla Predebon
16 Kyra Simon
17 Makenzie Weale*
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