The Magpies squandered an opportunity to reach the last four of the League Cup for the first time since 1976 when they lost 1-0 to Championship side Brentford on Tuesday evening, and now face a daunting run of fixtures, with a trip to Manchester City on Saturday (kick-off 8pm GMT) before hosting league leaders Liverpool and Leicester City, who are currently second.
But Bruce says his players must embrace the opportunity to bounce back against three of the country's top teams, starting at the Etihad Stadium against Pep Guardiola's all-star side - last season's Premier League runners-up, and the champions in the previous two seasons.
"It's a difficult challenge - we're playing one of the best teams in the world - but we've got to make sure that we get over the disappointment of the other night, roll our sleeves up and show what we're made of," said Bruce. "This league is unforgiving, it's very, very difficult at times, so you have to get ready for the challenge.
He added: "That's the Premier League, that's what it is, that's what faces us. We managed to get a result against them last year - and then got heavily beaten at the Ethiad - but we're playing against one of the great teams so let's dust ourselves down, get over what happened the other night and get ready for a huge challenge.
"What better place to try and respond? We know how difficult it will be but we have to be ready for that challenge. We've had a disappointing week, we're hugely disappointed in what's happened the other night - hugely, and none more so than me - but here's a wonderful opportunity."
Bruce - who revealed that goalkeeper Martin Dúbravka is now "not far away" from returning from his pre-season heel injury to challenge Karl Darlow - is hoping to have Federico Fernández available after the Argentine was substituted at half-time in last weekend's draw with Fulham, having only recently recovered from Covid-19.
"We'll see how he is," said the Magpies' head coach when asked if Fernández could feature on Boxing Day. "I sincerely hope so, but he was very fatigued after real soreness of his muscles and was in no fit state to play.
"I don't think I've worked with a better pro than Fede, so for him to have the effects just goes to show that it affects different people in different ways. But yes, I hope I have at least him back because at centre bank we've been a little bit short."
United were hit by an outbreak of the virus earlier this month, and Bruce provided an update on the condition of Allan Saint-Maximin and captain Jamaal Lascelles, who it has now been confirmed have also been suffering from the after-effects of coronavirus.
"There's been a lot written and I'll try and put the record straight," he said. "They're not ready to return until the doctors tell us. Everybody's different with the symptoms, but we expect them to be back; how long, I really can't put a timeframe on.
"(It will) probably be Jamaal before Allan, but we hope that we can see an improvement in both of them and they can join the squad in the next week, two weeks, maybe.
"It's been well documented how difficult it's been over the last week, ten days. We're obviously desperately short in central defensive areas, where it's hit most badly.
"We'll look to freshen it up. I think it's vitally important that you do that because obviously we've got some big games coming up."
