The Swedish striker scored the winner when the sides last met in the League Cup final in March as Newcastle lifted their first domestic trophy for 70 years.
But Isak is yet to feature for Eddie Howe’s men this season as he seeks an exit from Tyneside.
Liverpool are the likely destination if Isak does leave before the transfer window closes in a week’s time.
The Reds have reportedly had one bid of £110 million ($149 million) rejected as Newcastle want a British transfer record £150 million.
Adding to the Magpies’ frustration is the fact the Premier League champions also won the race to sign Ekitike, who Newcastle had lined up as a potential Isak replacement.
Liverpool boss Arne Slot named new signings Ekitike and Florian Wirtz, alongside Cody Gakpo and Mohamed Salah in an ultra-offensive lineup that saw Dominik Szoboszlai deputise as a makeshift right-back.
After failing to land a number of striker targets in the transfer market, Newcastle’s lack of a clinical number nine was exposed as they failed to break down 10-man Aston Villa in a 0-0 draw to begin their season last weekend.
And it cost them again during a dominant opening 30 minutes.
Roared on by a ferocious capacity crowd of over 50,000, Newcastle penned Liverpool inside their own half without finding the final finish.
Instead it was the visitors who took the lead completely against the run of play on 35 minutes.
Gravenberch took aim from well outside the area and powered an inch-perfect shot off the inside of the post.
It got even worse for Newcastle before the break as Gordon took out his frustration by charging late into Van Dijk and was dismissed after a VAR review showed his studs had raked down the Dutch defender’s Achilles.
Slot had not even taken his seat for the second half by the time his side doubled their lead 20 seconds in.
Ekitike made it two goals in as many Premier League games with a composed side-footed finish from Cody Gakpo’s pass.
Newcastle’s sense of injustice only increased when Ibrahima Konate escaped a second yellow card moments later for a push on Harvey Barnes.
But this time the home players and crowd channelled their anger more positively.
Minutes after being booked for taking his protests too far, a fired-up Guimaraes outmuscled Milos Kerkez to head in at the back post.
Liverpool struggled to make their man advantage count for the entirety of the second half and were made to pay.
Despite his lack of forward options, Howe has been reluctant to field Osula, but the young Dane netted just his second Premier League goal when he bundled the ball beyond Alisson from a Dan Burn flick-on.
Newcastle continued to charge forward in search of a memorable winner, only to be picked out by Liverpool’s attacking quality.
Salah’s pass was brilliantly dummied by Szoboszlai to leave Ngumoha unmarked to curl calmly into the far corner just days before his 17th birthday.
