Billed externally as a revenge match before Thursday night, the Storm spent Friday counting the costs of two big-name collisions during their win in the grand-final rematch.
Hughes will undergo surgery on Saturday after scans showed he had fractured his hand in a first-half collision with Nathan Cleary.
Nick Meaney will be out of action for up to six weeks with a fractured face, while Nelson Asofa-Solomona has suffered a concussion after the pair clashed heads.
In better news for Melbourne, winger Grant Anderson and second-rower Eliesa Katoa have both avoided knee injuries after it was initially feared they would spend time on the sidelines.
Five-eighth Cameron Munster has also avoided a charge from the NRL judiciary, cleared of a hip-drop tackle while trying to chase down arch-nemesis Liam Martin.
Still, the heavy injury toll came after Hughes initially played through the pain of a broken hand, following his painful-but-spectacular collision with Cleary.
While Cleary was immediately ruled out of the game for Penrith with a concussion and stood down for 11 days, reigning Dally M medallist Hughes clutched at his hand in pain.
Hughes stayed on the field, set up a try and controlled Melbourne's kicking in the pulsating 30-24 win, but will now miss games against St George Illawarra and Manly.
Utility Tyran Wishart or 22-year-old Jonah Pezet would be favoured to join Munster in Melbourne's halves next week.
Asofa-Solomona will also sit out the Dragons clash, after he initially passed a HIA following the head clash with Meaney in the first half of the victory.
The prop then failed an assessment post match, forcing him to enter concussion protocols.Â
Asofa-Solomona had been playing his first NRL game back since being banned from last year's grand final over a high shot.
Meanwhile, Penrith also have decisions to make in the halves after Cleary's concussion.
Blaize Talagi came off the bench to fill in at five-eighth on Thursday night, with Jack Cole slotting in at halfback.
The pair have started only 10 NRL games in the halves between them, with Brad Schneider a slightly more experienced option available to come into the team next week.
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