Although Ademola Lookman's tidy finish had put the Foxes ahead on 19 minutes, a brace from Bruno Guimarães, including a winner in the final minute of added time, denied Brendan Rodgers' men a point on Tyneside.
There were eight changes from the heroic 2-1 victory over PSV Eindhoven in the Netherlands on Thursday, sealing the Club a place in the semi-finals of the UEFA Europa Conference League. In came James Justin, Daniel Amartey, Çağlar Söyüncü, Luke Thomas, Papy Mendy and Patson Daka.
Ayoze Pérez and Lookman – lauded for their impacts from the bench in midweek – were also back in the XI. Leicester had won on their previous five visits to St. James' Park but knew the challenge would be an altogether different proposition against Eddie Howe's rejuvenated Magpies.
A boisterous home crowd greeted them in the North East and, inside 60 seconds, Amartey was forced to fell Miguel Almirón midway through City's half and collect the game's first caution from referee Jarred Gillett. Jonjo Shelvey's subsequent free-kick was audacious, but straight at Kasper Schmeichel.
There was a brief silence around the 52,000-capacity home of Newcastle when Martin Dúbravka and Dan Burn clattered into one another, trying to prevent Daka from capitalising on Söyüncü's hopeful forward ball. Burn required attention from the Newcastle medical team and eventually was able to continue.
Fifteen minutes in, Fabian Schär's cross towards the far post was belted over the crossbar by Joelinton. It was 1-0 to the Foxes on 19 minutes, though. It came in some style too. Kiernan Dewsbury-Hall's corner was fizzed in low to Pérez, lurking at the near post in front of the Gallowgate Stand.
After his excellent assist for City's equaliser in Eindhoven less than 72 hours earlier, Leicester's No.17 flicked the ball back for Lookman to calmly sweep the ball beyond Dúbravka and into the back of the net. A reward for the 3,000-strong away following which had made the near-200 mile trip from Leicester.
There was almost a goal for Pérez too when Youri Tielemans recycled the ball into his path, but the Spaniard found Burn's thigh in his way. Allan Saint-Maximin immediately looked to pounce once the following corner broke down. The raking right boot of Dewsbury-Hall, however, stopped him in his tracks.
On the half hour, parity was restored, although it needed a lengthy VAR intervention to confirm the decision. Shelvey's corner was headed down by Burn for Guimarães at the far post. The Brazil international, signed from Lyon in the winter, then prodded it underneath the grasp of Schmeichel.
The referee initially disallowed it, but after consulting the pitchside monitor, elected to overturn his original decision and award the goal. The locals were buoyed in the Easter Sunday sunshine and the Magpies responded with Guimarães' lofted ball being nodded straight at Schmeichel by Matt Targett.
Joelinton's cross was then glanced wide by former City forward Chris Wood, before Dewsbury-Hall drilled a long-ranger into the gloves of Dúbravka. Leicester were unchanged in the second half as, within the opening five minutes, Saint-Maximin twice missed the target from the border of City's penalty area.
Some admirable defending from Emil Krafth and then Guimarães prevented Lookman and Dewsbury-Hall from testing Dúbravka, before Justin took down Thomas' high ball and found the Magpies' No.1 in his way from a tight angle.
On the hour, Rodgers made his first change, with James Maddison replacing Pérez. Moments later, the Northern Irishman made another move, introducing Harvey Barnes for Lookman. Howe's response was to bring on Joe Willock and Jacob Murphy. Wood and Almirón departed.
The game had become stuck in a midfield quagmire so another intervention from the manager saw Kelechi Iheanacho take Daka's place for the final 13 minutes on Tyneside. It added another fresh pair of legs onto the field of play for Leicester against a side who hadn't played in the nine days beforehand.
With Maddison, Iheanacho and Maddison dragging three Magpies players back to the half-way line for Targett's corner, Burn's header then lacked the power or the accuracy it needed to concern Schmeichel in the City net.
At the opposite end, Barnes slipped in fellow Academy graduate Dewsbury-Hall, who had the room to skid the ball in low to Iheanacho. The Nigerian's flicked finish was an inventive idea, but under pressure from Burn, it was comfortably scooped up by Dúbravka with five minutes of normal time remaining.
City were probing, but often found a resolute Newcastle backline in their way. Maddison's corner, inside the four added minutes, offered an opportunity. The ball into the box, however, was touched away from Söyüncü's head before he could apply a finish. Within mere seconds, at the very end of the clash, Newcastle were ahead. Their winner came after Willock charged down the left flank and located Guimarães, who headed into the top corner.
Major moment
The beneficiaries of a late winner at PSV on Thursday, Leicester were the victims of one in Newcastle three days later, as Bruno Guimarães' late second secured all three Premier League points for the Magpies.
Who impressed?
Former Leicester City star Simon Grayson said during the LCFC Radio live coverage: "I will go for Papy Mendy because I think he picked up second balls, he kept it ticking over. I thought James Justin was very good over on the right-hand side, but Mendy held a lot of it together. He kept it simple."
Where does it leave us?
City are ninth in the Premier League on 40 points with a goal difference of -4.
Coming up...
The fixture schedule continues for the Foxes on Wednesday night with a trip to Goodison Park to tackle Everton (7:45pm kick-off). Aston Villa are the visitors to King Power Stadium next Saturday (3pm kick-off), before City host Roma in the UECL last four on Thursday 28 April (8pm kick-off).
The details...
All times BST.