Manchester City dashed the dreams of Salford's former Manchester United star owners with an 8-0 FA Cup rout Saturday, while Liverpool cruised into the fourth round with a 4-0 victory over Accrington Stanley.
Chelsea were among the other big winners with a 5-0 demolition of Morecambe Wanderers.
Brentford were the only Premier League side to fall to lower-league opposition as Plymouth Argyle, who sit bottom of the Championship, stunned the Bees 1-0 thanks to Morgan Whittaker's late winner.
League Two Salford have risen through the non-league ranks since investment from David Beckham, Gary and Phil Neville, Paul Scholes, Ryan Giggs and Nicky Butt began in 2014.
Scholes, Butt and director of football Giggs were in attendance at the Etihad but were denied a night to rival their best during glorious playing careers at Old Trafford.
Pep Guardiola made wholesale changes as Erling Haaland was afforded a rest.
Jeremy Doku opened the scoring after just eight minutes before youngsters Divin Mubama and Nico O'Reilly made it 3-0 before half-time.
Jack Grealish scored his first City goal for over a year from the penalty spot, while Doku also netted from the spot.
But James McAtee, who had only scored once for City previously, earned man-of-the-match with a 20-minute second half hat-trick.
There was never any hint of an upset at Anfield either despite Arne Slot making eight changes for Liverpool.
Trent Alexander-Arnold was named captain in the absence of Virgil van Dijk and led by example after being criticized for his display in a 2-2 draw against United last weekend.
Slot had warned the Premier League leaders that a trip to Anfield would be Accrington's "Champions League final".
A mammoth 86 league positions behind Liverpool in the 92-team English league system, Stanley held out for nearly half an hour before Diogo Jota was left with a simple task to tap in from Darwin Nunez's low cross.
Alexander-Arnold then stepped forward to double the lead with a sumptuous hit into the top corner from outside the box.
"I could talk for hours about that (goal), unbelievable," said Slot said.
"The biggest compliment Trent could get was the reaction of everyone after the United game.
"Every player around the world, maybe except for a few, has a bad game and that is completely normal, but the moment Trent has one, everyone has an opinion about it."
Jayden Danns made it 3-0 before Federico Chiesa netted his first Liverpool goal after an injury-hit start to his time in England.
Joao Felix was the star of the show for Chelsea as he got a rare chance to deputize for Cole Palmer.
The Portuguese international and Tosin Adarabioyo both scored twice, while Christopher Nkunku made up for missing an early penalty by netting his 13th goal of the season.
Only Liverpool have taken more points at home than Brentford in the Premier League this season, while Plymouth had not won away from home all campaign.
Yet against the odds Argyle, who sacked former England captain Wayne Rooney 12 days ago, held out and hit Thomas Frank's men with a sucker punch when Whittaker blasted in from outside the area nine minutes from time.
"I have pride in everybody, and I'm pleased for the supporters. It's a big day for us," said caretaker Plymouth boss Kevin Nancekivell.
"The FA Cup brings that romance and we've put a little bit of history in it today by getting the win."
High-flying Nottingham Forest continued their excellent season with a comfortable 2-0 win over Luton Town.
Brighton and Hove Albion were 4-0 winners at Norwich City as Georginio Rutter struck twice.
Bournemouth shrugged off the loss of strikers Evanilson and Enes Unal to long-term injuries this week to roar back from 1-0 down to hammer West Bromwich Albion 5-1.
Leicester City went one better by hitting QPR for six in an eight-goal thriller at King Power.
Wolverhampton Wanderers' bright start under new boss Vitor Pereira continued as early goals from Rayan Ait-Nouri and Rodrigo Gomes secured a 2-1 win at Bristol City.
RESULTS
Birmingham 2 (Yokoyama 1, Dykes 77) Lincoln 1 (Makama 90-P)
Bournemouth 5 (Kluivert 27, Ouattara 34, 44, Semenyo 47, Jebbison 90+2) West Brom 1 (Taylor 14)
Brentford 0 Plymouth 1 (Whittaker 82)
Bristol 1 (Twine 45+1) Wolves 2 (Ait-Nouri 10, Gomes 21)
Chelsea 5 (Adarabioyo 39, 70, Nkunku 50, Felix 75, 77) Morecambe 0
Coventry 1 (Kitching 26) Sheffield Wednesday 1 (Musaba 90+3) aet
Coventry won 4-3 on penalties
Exeter 3 (Mitchell 22, 40, Harper 64) Oxford 1 (Phillips 14)
Leeds 1 (Ramazani 59) Harrogate 0
Leicester 6 (Justin 8, 63, Mavididi 35, Buonanotte 38, Vardy 51-P, Faes 90+3) QPR 2 (Varane 18, Kolli 45+2)
Liverpool 4 (Jota 29, Alexander-Arnold 45, Danns 76, Chiesa 90) Accrington 0
Man City 8 (Doku 8, 69-P, Mubama 20, O'Reilly 43, Grealish 49-P, McAtee 62, 72, 81) Salford 0
Middlesbrough 0 Blackburn 1 (Weimann 70)
Norwich 0 Brighton 4 (Rutter 37, 45+2, Enciso 59, March 74)
Forest 2 (Yates 40, Sosa 68) Luton 0
Reading 1 (Wing 77) Burnley 3 (Foster 71, Flemming 100, 109) aet
Sunderland 1 (Aleksic 64) Stoke 2 (Cannon 4-P, Ennis 112) aet
Friday
Villa 2 (Onana 71, Rogers 76) West Ham 1 (Paqueta 9)
Wycombe 2 (Hanlan 17, Bradley 27) Portsmouth 0
Thursday
Everton 2 (Beto 42, Ndiaye 90+8-P) Peterborough 0
Fulham 4 (Muniz 26, Jimenez 49-P, Andersen 65, Castagne 85) Watford 1 (Vata 33)
Sheffield Utd 0 Cardiff 1 (Ashford 19)
