Manager Brendan Rodgers made two changes to his side, with Portugal star Ricardo Pereira replacing left-back Luke Thomas and Marc Albrighton coming in for Jonny Evans as a part of a late change to the starting XI. That saw Albrighton take up a left-sided wing-back position, while Timothy Castagne played as a right-sided centre-back.
It then took two decent blocks - from Castagne and then Albrighton - to turn away a brace of efforts from Matt Ritchie, while Wesley Fofana followed up with an important headed clearance with several Newcastle men lurking as the Magpies looked to capitalise on their period of possession.
Another set-play situation for Newcastle, this time delivered by Jonjo Shelvey, saw Federico Fernández flick a header wide just before the quarter-hour mark during an end-to-end opening passage on Filbert Way.
Newcastle were productive on the counter-attack and after Callum Wilson paced down the right-hand channel, he was able to locate the run of Allan Saint-Maximin, whose placed finish was turned away by a superb stop from Denmark star Kasper Schmeichel.
But the visiting side continued to press and on 22 minutes, they took the lead. Joe Willock seized on a loose ball and raced through to fire a deflected effort into the bottom corner to hand his side a 1-0 lead.
City were looking for an immediate reply and first went close after Youri Tielemans picked out Maddison on the edge of the box with a floated corner, however the No.10's first-time effort was blocked, and then Dúbravka made a fine point-blank save to deny Fofana's powerful header.
However, after that opportunity to level matters, Newcastle struck again at the other end as Paul Dummett rose to meet a Ritchie delivery to double his side's advantage.
Two chances in quick succession to halve the deficit came before the interval, with Maddison having an attempt blocked before in-form Kelechi Iheanacho forced Dúbravka into another smart stop on the goal-line.
Right at the end of the first period, just as the fourth official's board showed one added minute, Maddison scooped a pass into the path of Vardy, who tried to lift the ball over the onrushing Dúbravka, but was thwarted by the Magpies shot-stopper.
Three minutes into the second half, Maddison flicked Iheanacho's cross onto the roof of the net, before Schmeichel gathered Jacob Murphy's low attempt shortly after.
The Foxes continued to show determination, with Maddison's free-kick deflecting just inches wide before Wilfred Ndidi nodded just off target from the resulting corner.
On 63 minutes, Ndidi made way as former Newcastle forward Ayoze Pérez was brought on to add fresh legs to the City attack, however Steve Bruce's side extended their advantage a minute later when Wilson latched onto Ritchie's pass before rounding Schmeichel and side-footing into the back of the net.
Six minutes after his introduction, Pérez came close to pulling a goal back for Leicester, only for Dúbravka to claw the ball out of the top corner. Before the resulting corner was taken, Rodgers made a second substitution with Academy graduate Thomas replacing Ricardo.
Newcastle made it 4-0 not long after, though, with Wilson collecting Miguel Almirón's pass before converting at the second attempt after his initial effort struck the inside of the post.
City tried to respond, with Maddison and Vardy both having shots blocked with just under 15 minutes of normal time remaining. That proved to be Maddison's last action of the night, with Papy Mendy coming on as his replacement.
A deep pass from Iheanacho then found Tielemans on 78 minutes, only for the Belgium international midfielder to hook his strike over the bar and behind for a goal-kick.
With 10 minutes to play, a well-worked move involving Thomas and Vardy eventually saw the ball fall to Albrighton, who arrowed a fine shot into the top corner for 4-1.
A right-footed curler from Vardy then flew off target with seven minutes of normal time remaining, and as City enjoyed plenty of the ball in the closing stages, a second of the night arrived as Iheanacho drove the ball into the bottom corner for his 11th Premier League strike of the campaign.
A third goal nearly arrived for City, however Dúbravka - not for the first time on the evening - spread himself to prevent Pérez from drilling home at the far post in injury time.
Wesley Fofana was denied by Martin Dúbravka in the first period with the score at 1-0.
With the scoreboard showing 1-0 after Joe Willock's opener midway through the first half, City had a huge chance to level matters via the head of Wesley Fofana.
However, the France Under-21s defender was denied by Martin Dúbravka, who made a brilliant save, and Newcastle added three more goals to put the game beyond the hosts, despite late efforts from Marc Albrighton and Kelechi Iheanacho.
Where do we stand?
Brendan Rodgers' men are third in the table with three Premier League games to play.
After their 35th Premier League match of the campaign, City remain third in the table with three matches to play.
The Nigeria striker was once again on the scoresheet for City, but couldn't prevent them from suffering a 4-2 loss.
The Foxes contest their penultimate Premier League away match of the 2020/21 season on Tuesday when they head to Old Trafford to face Manchester United (6pm kick-off) ahead of a Wembley Stadium showdown with Chelsea in the Emirates FA Cup Final four days later (5:15pm kick-off).
All times BST.
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