Soudal Quick-Step's Evenepoel first attacked with about 34 kilometres left with Ineos Grenadiers' Tom Pidcock (23) joining him at the front. But Evenepoel attacked again on the next climb to leave the Briton behind with 30 kilometres to go.
Despite the rain and wet roads, Evenepoel looked like he was in his element and he reached the top of Cote de la Roche aux Faucons, the final climb, with a lead of one minute and 18 seconds.
As he finished his final descent, he was already celebrating his win with the Soudal Quick-Step car before he crossed the finish line to become the first rider to win the race in consecutive years since Michele Bartoli in 1998.
"It was a difficult race, with the rain the roads were quite slippery. My back wheel went a bit like it did last year (on a turn)," Evenepoel said.
"But we stayed calm, handled it well and stuck to our plan, which was to attack after La Redoute and I knew I should go for it on the new unclassified climb. That was where I had to create the biggest difference on the chasers."
The world champion, wearing number one on his rainbow jersey, urged the crowd to raise the volume as he crossed the finish line with his arms outstretched.
"Winning with this beautiful jersey is wonderful. I said I wanted the picture with the jersey to put in my bedroom," Evenepoel added.
Pidcock finished second after beating Santiago Buitrago (23) in a sprint to the finish, more than a minute behind Evenepoel, while Ben Healy (22) was fourth.
Pidcock said he did not risk chasing Evenepoel on the last attack as he was worried about running out of steam and losing a podium place.
"I was on the limit and I knew I could either commit full gas and maybe end up with nothing or wait a bit and try and go for second and I still got second. So I think the plan paid off," he said.
Pogacar, who won the event in 2021, was looking to add a second Monuments classic to his list of victories this season after winning the Tour of Flanders but he was involved in a crash with EF Education-EasyPost's Mikkel Honore (26) 84.5 kilometres in.
Pogacar's teammates initially stopped and waited for the two-time Tour de France winner to resume before rejoining the bunch.
UAE Team Emirates' medical director Adrian Rotunno later said the Slovenian had suffered a wrist injury, adding that scans at a hospital revealed he had suffered fractures and he would undergo surgery with a specialist hand surgeon in Genk.
"The surgery on Tadej's scaphoid was successful and he will travel home tomorrow for recovery and rehabilitation," said Medical Director Adrian Rotunno.
Pogaca had planned a four-week break from competitive racing after Liege-Bastogne-Liege.
In the women's race earlier in the day, Demi Vollering (26) beat Elisa Longo Borghini (31) in a two-up sprint to cap off an incredible seven days for the Dutch rider, who was also victorious in the other two Ardennes classics; La Fleche Wallone and Amstel Gold Race.
