Tottenham are bottom of the league after zero wins, two draws and three losses under De Zerbi who has conjured up just two goals so far.
It is their worst-ever start to a Premier League season after five games, beating their previous low of two points in 2008/09.
De Zerbi is on the verge of being sacked by a Spurs board who are all out of ideas as the club continues to fall off a cliff despite investment and manager changes.
Speaking to Betfair, Shearer has spoken on what he believes is the biggest game of the weekend as Tottenham desperately try to kick-start their campaign against the Red Devils.
"I think it's possibly one of the biggest games of the weekend, I know you've got Liverpool v City, which everyone's going to have eyes on for obvious reasons, but I think in terms of the size of the result, this is the biggest one of the weekend because if either club were to lose in whatever fashion they were to lose, then it could determine someone's job. Unfortunately, I think it's that big a game in that matter.
"Spurs can’t afford to slip up again. I think being at bottom of the league and they spent a fortune and they're not playing good football. They brought players in to try and change what happened last year and the year before and they're in a worse position at the minute. De Zerbi would have been chomping at the bit to have a game but also it would have got him to work with a few more of his players, albeit there would be a lot away on international duty. So, it's a massive game for Spurs and for Man United.
He continued: "It really depends on the manner of the results as to what action the Spurs board might potentially take in the near future, as at the moment it's not okay. No one wants to lose games, but I guess it's the manner and how you lose them or your manner how you don't win them, which is the standout. There have been little glimpses of improvement and we will have to see what reaction they get at the weekend, but he'll know, and everyone else knows, that he needs a result. He can't afford to play Man United and be beaten 2 or 3-0, that's for sure."
Tottenham spent around £330M on 10 new players over the summer and none have worked out so far. De Zerbi needs a win against United and anything less could mean him packing his bags after a dismal spell in North London.