The Briton banished previous near misses as he edged Swiss rider Marc Hirschi at the line, with Belgian Tiesj Benoot rolling in third to complete the podium.
Last year Pidcock was third. In 2021 he lost in a long-delayed photo-finish to Wout van Aert, amid suggestions that the camera had not been aligned with the finish line.
"I was going to say 'It's great to win for the second time' but that might create some controversy," Pidcock said.
"It feels really good, this year's been so tough, I made big sacrifices at the start of the year, been away from home so much, so now to finally put it together, to get the hands in the air means a lot and this race I've always loved racing, it's pretty special."
The podium trio had been part of a quartet who escaped from a late breakaway and stayed just clear to the line.
Pidcock, who rides for Ineos, completed the twisty, hilly 253.6-kilometre run from Maastricht to Valkenburg in five hours, 58 minutes and 17 seconds.
The next 10 finishers were all credited with the same time. The fast-closing peloton was 11 seconds back.
The Dutch one-day classic broke up the spring run of three of cycling's five super-long monuments.
Dutch rider Mathieu van der Poel dominated the last two Sundays with wins at the Tour of Flanders and Paris-Roubaix. He can add a third monument on April 21 at Liege-Bastogne-Liege.
'Shoulder pain'
When a dozen riders broke away on the Keutenberg climb with 30 kilometres to go, the Visma leader was content to wait in the pack. But the escapees nursed a small advantage to the line.
Pidcock said he was still feeling pain in his shoulder after a crash preparing for the Tour of the Basque Country, which he then skipped, and in his hand, after a fall in Paris-Roubaix.
"This week I was struggling to sprint, I had a lot of shoulder pain so I couldn't hold my bars properly so I was not so confident but it was how it was going to end up," he said.
Last year's winner Tadej Pogacar is skipping the spring classics to focus on preparing for a Giro d'Italia-Tour de France double.
Earlier, Marianne Vos grabbed victory in a shortened women's race as Lorena Wiebes put her hands in the air to early, sitting up to celebrate before the finish.
Vos, who rides for Visma, exploited the error by her Dutch compatriot Wiebes of SD Worx to win the sprint.
"It's a shame for Lorena, but I'm happy with this victory," said Vos.
Norwegian Ingvild Gaskjenn was third.
The race was held up for an hour, after an accident involving a police motorbike escorting the peloton.
The riders held an improvised picnic before setting off again on a shortened route that avoided the crash site.
