Munster is set to undergo surgery on knee cartilage and miss at least a month while Hughes is another to join the Storm casualty ward due to "ongoing hamstring soreness".
Tyran Wishart has been tasked with covering No.6 Munster for their Friday night clash with the Sydney Roosters, while Trent Toelau will play his first game at halfback for the Storm.
While the extent of Queensland captain Munster's injury was revealed in scans on Monday, the loss of Hughes - second in the competition in try assists - is another blow in a wretched season for last year's grand finalists.
Melbourne will be hopeful of Hughes only missing the match against the third-placed Roosters at Allianz Stadium so he can resume his partnership with Wishart.
Sitting 10th on the ladder, the Storm are still a chance of playing finals with six rounds and a bye left in their campaign, but they face looming matches against big guns South Sydney, Penrith, Manly and Cronulla.
Wishart was among the team's best in the tight win over the Titans last round and centre Nick Meaney said the utility was the perfect player to fill Munster's No.6 jersey.
"It's never nice to see one of your fellow teammates go down and especially this time of year when we need him the most, it's pretty tough," Meaney told AAP.
"Obviously he's (Munster) a very experienced player, he's played on the biggest stages in the game.
"Wishart's a great player, a great eyes-up footy player just like Mun (Munster), so I've got no doubt that Wishy's going to do a good job while he's in there.
"It's up to everyone else to pick up the load and it's not an individual sport, it's a team sport, so it's not all on one guy's shoulders."
Wishart covered for the injured Munster for eight mid-season matches in 2024, steering the Storm to seven wins as they played their way into a losing grand final against the Panthers.
Meaney said that experience had built belief Wishart was up to the task, with their season on the line.
"I think people forget that he had that great year in 2024 when he played most of the year when Mun was out," said Meaney.
"He had probably one of his best years to date and that was in the No.6 jersey, so, I've got full faith with him.
"I've played alongside him before when he's played halfback when (Jahrome) Hughes is out, and he's a great defender and a great runner of the ball."
Meaney himself missed five weeks with a calf injury but returned to play a crucial role against Gold Coast.
He scored in the 79th minute to break an 18-18 deadlock and secure Melbourne victory.
"The lungs were hurting and the legs were a bit heavy, but it was good to be back out there," he said.
"I remember thinking in that last four or five minutes, I just didn't want the game to go into overtime because the body wasn't feeling too great, but everyone did their role leading up to it and I pretty much just dove over."
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