The 195km route from the Hungarian capital Budapest was relatively uneventful until the final 5.6km-long ascent in the town's citadel.
A crash with less than 2km remaining blocked around a third of the peloton and prevented several of the top names from challenging for the sprint victory.
Tokyo 2020 Olympian Van der Poel pulled clear in the last 100m to the line to outsprint Giro debutant Biniam Girmay and claim stage and the leader's pink jersey.
Australian Caleb Ewan was in contention for the win on the final climb but clipped Girmay's back wheel and fell sprawling to the tarmac just metres before the finish line.
Spain's Pello Bilbao rounded out the podium ahead of Magnus Cort of Denmark.
The second stage on Saturday will be a 9.2km time trial In Budapest, with van der Poel the last rider to start, shortly before 5pm CEST. The race will end on 29 May.
"I knew positioning would be the key to win today," Dutchman van der Poel said after the race.
"It was a bit difficult sometimes I got boxed in a few times on the final climb and it cost a lot of energy to catch the guys in front of me. In the final, I just launched my sprint and it was pretty close because the legs were full of lactate. But I'm really happy."
Now 27 years old, he took part in the mountain bike (MTB) event at the Tokyo 2020 Olympics in 2021.
Giro d'Italia: Stage 1 Results
- Mathieu van der Poel (Alpecin-Fenix) 4h 35' 28"
- Biniam Girmay (Intermarche-Wanty-Gobert) +00
- Pello Bilbao (Bahrain Victorious) +00
- Magnus Cort (EF Education-EasyPost) +00
- Wilco Kelderman (BORA-hansgrohe) +00
The General Classification standings mirror the first stage results, with van der Poel holding the overall leaders' pink jersey (Maglia Rosa).
Giro d'Italia race schedule and how to watch
The 2022 Giro began on Friday 6th May 2022, and will conclude on 29th May.
6 May: Stage 1 - Budapest-Visegrad (195 km) - Won by Mathieu van der Poel (Alpecin-Fenix), who also claims the overall lead.
7 May: Budapest-Budapest (Time trial, 9.2km)
8 May: Kaposvar-Belatonfured (201 km)
9 May: Rest day
10 May: Avola-Etna (166 km)
11 May: Catania-Messina (172 km)
12 May: Palmi-Scalea (192 km)
13 May: Diamante-Potenza (198 km)
14 May: Napoli-Napoli (149 km)
15 May: Isernia-Blockhaus (187 km)
16 May: rest day
17 May: Pescara-Jesi (194 km)
18 May: Santarcangelo di Romagna-Reggio Emilia (201 km)
19 May: Parma-Genova (186 km)
20 May: Sanremo-Cuneo (157 km)
21 May: Santena-Torino (153 km)
22 May: Rivarolo Canavese-Cogne (177 km)
23 May: rest day
24 May: Salo-Aprica (193 km)
25 May: Ponte di Legno-Lavarone (165 km)
26 May: Borgo Valsugana-Treviso (146 km)
27 May: Marano Lagunare-Santuario di Castelmonte (178 km)
28 May: Belluno-Marmolada (Passo Fedala)
29 May: Verona-Verona (Time trial, 17.1km)
How to watch Giro d'Italia 2022
Every stage of the race is filmed and made available for live TV coverage and streaming via local broadcast partners in different regions. In Europe, this is via Eurosport and Discovery+, with RAI Sport in Italy showing the coverage for viewers in the host nation. GCN+ in USA/Canada, SBS TV in Australia, and BeIN Sports are other major broadcasters offering television and livestream coverage. Full details of broadcasting and race updates are also on the official giroditalia.it website.