The Slovenian, who has now won both monuments this year, attacked on the penultimate cobbled climb of the race to drop another three-time winner, Van der Poel and the Dutchman was unable to live with the pace, finishing alone in second place, 34 seconds back.
Debutant Remco Evenepoel, who only announced he would ride 'De Ronde' in midweek, stayed with the pair for as long as he could, but was dropped on the first time up the brutal Paterberg.
He was the first Belgian finisher, followed by Wout van Aert in fourth and Denmark's Mads Pedersen, who finished in fifth.
All of the top five finished alone, in what was one of the most attritional editions of the monument.
“It was a crazy race,” Pogacar said afterwards. “I don’t race too much, so when I race there’s pressure to win. So far, everything went perfect so I can be more than happy. Next week (Paris-Roubaix) I’ll be motivated and try to enjoy the cobbles.”
Pogacar, Van der Poel, and Evenepoel made the decisive gap for the peloton on the penultimate ascent of the Oude Kwaremont, where Wout van Aert and Mads Pedersen remained close to the trio but still couldn't follow.
The Paterberg then subsequently also became too much for Evenepoel as Pogačar and Van der Poel raced clear ahead of the Koppenberg.
Evenepoel's time trialling expertise allowed him to come agonisingly close to making contact on numerous occasions, but in the end, he couldn't bridge the gap to the powerful duo up front.
Pogacar then, as expected, launched a fierce attack on the final ascent of the Kwaremont and carved out a six-second gap to Van der Poel at the top, before he then extinguished all hopes of a Dutch hope on Paterberg as Pogačar fought off Van der Poel’s spirited chase.
Thanks to the win, Pogacar joined an elite club of riders to have won the race three times, alongside Van der Poel, Fabian Cancellara, Lotte Kopecky, Tom Boonen, Johan Museeuw, Eric Leman, Fiorenzo Magni, and Achiel Buysse.