The former Liverpool star believes both players are talented, but makes the Red Devils too offensive, leaving them open at the back.
United have conceded five goals from their opening two Premier League matches with Fernandes and Pogba starting in midfield.
Murphy, who has expressed doubts over Fernandes and Pogba playing together in the past, told talkSPORT: "Initially, I said when Fernandes came in it was going to be a problem, and I still think it is a problem.
"Pogba and Fernandes in the same team makes them too offensive. Against a better opposition, you'll get found out. They're both brilliant technicians and creative footballers.
"Their defensive mindset is reactive, not proactive. They don't spot danger. They react afterwards. They see it and think, 'I better get back'. It's not natural for them.
"They only time I've ever seen Pogba defend was for France under [Didier] Deschamps when he was next to [N'Golo] Kante and put in a hell of a shift against Belgium [at the 2018 World Cup].
"But generally, he's a creative player, he's a brilliant player. I don't think moving forward, United are going to challenge for the title.
"I'm not talking about top four, I'm talking about getting back to competing for the title by having five offensive match winners in the team - I just don't think you can do it unless they change their defenders.
"They're not going to challenge for the title while playing those two in midfield."
Meanwhile, Murphy believes United's new £35million signing Donny van de Beek is more suited to cope with the defensive responsibilities in midfield.
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He said: "Then the question arises about Van de Beek.
"If you watch him, and I've watched him a lot, he is proactive with his defending.
"He is a box-to-box, super fit, all round midfielder who can do things defensively that those two [Fernandes and Pogba] don't want to do.
"To win the title again, if those two play together in a midfield three against the best five teams in the league, I don't think they'll win the league."
Danny Murphy insists Manchester United will not challenge for a Premier League title with Bruno Fernandes and Paul Pogba in the same team.