McLean strained his right quadriceps muscle in the warm-up on Saturday at Central Coast Stadium, where the Blues were holding their final session before flying to Melbourne later that day.
A handful of team staff attended to the Penrith left centre, who came into camp after suffering a minor ankle injury against Wests Tigers last Sunday.
The 20-year-old had been restricted in his training loads this week, but was on track to shake off his ankle issue by Wednesday.
But after going down on Saturday, McLean left the pitch and is expected to be sidelined for between seven and 10 days.
Missing Origin II is a devastating blow for rising star McLean, who was electric on debut from the bench in the Blues' game-one win.
"He's obviously very disappointed," said NSW football manager Frank Ponissi.
"He's worked so hard the last few days to get his ankle right and he was feeling fantastic going into the session. For this to happen is really disappointing."
McLean had been due to start for the first time after Stephen Crichton succumbed to a shoulder issue, but will be replaced in the centres by Tolu Koula.
That will free up room for code-hopping Sydney Roosters winger Nawaqanitawase to come into the starting side as part of a backline shake-up.
"We've trained that way for three sessions, Wednesday Thursday and also today," Ponissi said.
"So, if (the injury) was going to happen, it's the best possible way for it to happen."
A debut at the MCG on Wednesday night is yet another string in the bow for former Olympian and Wallabies star Nawaqanitawase, who hops codes back to rugby union next year.
Nawaqanitawase had initially been selected on Laurie Daley's six-man bench for Origin II, but would unlikely have played unless there was a mid-game injury.
The Blues will now seek permission from the NRL to name a player from outside their squad on the bench in Nawaqanitawase's place.
"We don't know who that player will be at this stage. It's something who will come in and cover that outside back (role) and sit on the bench," Ponissi said.
Blues five-eighth Mitch Moses returned to training with his teammates on Saturday and is expected to overcome his hamstring issue in time to play.
Moses was still wearing a compression sleeve on Saturday, but stretched and ran with ease.
He has not played since tweaking his hamstring two days before game one, but had always been confident in his ability to recover for Origin II.
"Mitch is good," Ponissi said.
"He and all the rest of the team got through OK. We're really happy about that."
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