Pogacar attacked the group of GC favourites with 12 kilometres of the final climb of the day, with no one able to respond, reeling in the break up Alpe d'Huez before sprinting clear of Richard Carapaz and Lenny Martinez in the final metres.
They would round off the podium with Remco Evenepoel two-and-a-half minutes down on the Slovenian, but keeping his podium push alive, whilst Isaac del Toro put a handful of seconds into French teenager Paul Seixas to keep the battle for the white jersey going into stage 20.
Pogacar not only set the climbing record on the fearsome 13.7km climb, but became just the second rider in Tour de France history to win in the yellow jersey after Geraint Thomas did it in 2018. He also put one minute into the record held by Marco Pantani since 1998.
Calm before the storm
With the roads being closed to cars 24 hours before the stage start on Alpe d'Huez, the start of the stage had an almost anti-climatic feel as the riders began in Gap.
The fireworks started early, though, with 42 riders going up the road as the climbing began out of the gate.
Four riders from EF Education-EasyPost, including stage 18 winner Richard Carapaz, were controlling things early from the front, whilst Lidl-Trek had a trio in there, with Mads Pedersen, the green jersey leader, looking to increase his lead despite the mountainous start. After Jonas Vingegaard crashed out last weekend, Visma Lease-a-Bike also had four men up the road with their strategy changed.
Behind, UAE Team Emirates-XRG set out their stall early in hunting for the win, as Nils Politt set a steady tempo.
The large group gained an advantage of 1:23 as they topped Col Bayard, with Valentin Paret-Peintre taking over the King of the Mountains (KOM) classification on the road after outsprinting Carapaz as their personal duel intensified.
Sickness has been rife within Pogacar's team over the last few days, with Brandon McNulty abandoning on Thursday. But there was good news for the beleaguered squad, as Adam Yates, who suffered from gastric issues on Wednesday, was looking better, getting himself in the 42-man group. Tim Wellens was dropped early, suggesting the sickness had moved on.
Gap increases
Lidl-Trek and EF Education-EasyPost took up the pacing duties for the second climb of the day - a 7.5-kilometre, 8.5% slog up Le Col du Noyer - as their conflicting interests caused disagreements.
Quinn Simmons, in his role as disgruntled domestique for Pedersen's ambitions, wanted to keep it steady for his leader, whilst Ben Healy and Sean Quinn were looking to up it in Carapaz's bid for KOM points.
The Ecuadorian rider sat eight points off Paret-Peintre as they reached the summit, and that deficit grew once again, as the Frenchman attacked with 200 metres to go for maximum points, extending the advantage to 10.
Back in the peloton, Red Bull - Bora-Hansgrohe started working alongside UAE Team Emirates-XRG to keep the gap from ballooning in the hopes Remco Evenepoel could win, but the break were driving on the flat, taking a maximum advantage of more than four minutes, keeping them in play for stage victory.
With 44km to go, Healy, who had worked hard for Carapaz over the last two days, blew up, leaving 40 to head into the intermediate sprint point as Josh Tarling from Netcompany INEOS was also dropped out the back.
Pedersen would take the full 25 points at the sprint, extending his lead over Jasper Philipsen to 47 points, all but securing the green jersey after a mammoth effort throughout the Tour de France from a rider who is not a pure sprinter.
Behind, with Lenny Martinez of Bahrain-Victorious in the break and, at one point, moving into the top five on general classification on the road, Tom Pidcock's Q36.5 team helped with pacing to limit the gap. Their work, along with Red Bull, gave Pogacar's squad some respite, playing into the hands of the superior Slovenian.
On to the Alpe
Before they reached the 21 hairpins of Alpe d'Huez, the riders still had the small matter of going over Col d'Ornon. Although 40 riders started the climb together at the front of the race, it wasn't long before that was whittled down through the pace-making of Visma and Bruno Armirail. Surprisingly, Paret-Peintre blew up early given his efforts over the last week, meaning he would take no more points in the KOM competition.
Carapaz would mop up the five points at the top, as the group shrunk to just 14 as they headed towards the final climb, leaving the polka dot jersey up for grabs heading into the final weekend.
It would be Carapaz, alongside Martinez and Sepp Kuss, who would be the final three from the breakaway to duke it out against each other, but the looming presence of Pogacar was the real threat as he ate into their three-and-a-half minute advantage consistently before overtaking them with 1.7km to go, all but sealing his fifth Tour de France victory in dominating fashion in front of an extraordinary crowd.
Pogacar now leads Evenepoel by seven minutes and x seconds with two stages to go, but the battle for the podium will rumble on. One big loser on the day was Juan Ayuso. Fifth before the stage, he was dropped on the lower slopes of Alpe d'Huez and shipped more than five minutes.
Saturday's stage sees the riders finish on the same slopes, albeit with a different route. They will tackle the Col de la Croix-de-Fer, Col du Telegraphe, Col du Galibier and the Col du Sarenne in a mammoth 170.9km day before they head to Paris.