The 21-year-old African rider was the fastest in a four-man sprint as he beat Christophe Laporte, second, with Dries van Gestel in third.
"It's unbelievable, amazing. I didn't expect this. We just changed my plan a few days ago on Friday. We just came for a good result. This race is amazing. Unbelievable," Girmay said after the finish.
With 24km to go, the Intermarche-Wanty-Gobert Materiaux rider joined a small breakaway which also included former Milan-San Remo winner Jasper Stuyven.
"I lost many places, especially on the first section and on the first cobblestones. I felt a bit uncomfortable. But after that, I felt better and better, I rode smart and followed. Then in the end, you know, everybody was waiting for (Wout) Van Aert so I played it a bit easy."
The Eritrean launched his final dash very early, but he managed to hold off Laporte and claim his biggest career's win:
"Of course I felt much better but also there were really strong guys with me so I was a bit afraid. But I felt confident in the last 250m. It's unbelievable, yeah."
Girmay, who won silver at the last under-23 men's world road race, became the first African rider to triumph at a classic race.
"The future has already changed for me and for all African riders," he said.
2022 Gent-Wevelgem - Results
- Biniam Girmay (ERI, Intermarche WG)
- Christophe Laporte (FRA, Jumbo-Visma)
- Dries van Gestel (BEL, Team TotalEnergies)
- Jasper Stuyven (BEL, Trek-Segafredo)
- Soren Andersen (DEN, Team DSM)