Wiebes launched off the wheel of teammate Coryn Rivera (Team DSM) in the last 150 metres of the run into Carugate to take the win, beating her only close competitor, second placed Emma Norsgaard (Movistar) and Marianne Vos (Jumbo-Visma) who took third.
The 21-year-old praised her team for their efforts to set up the victory, revealing the strategy was to target more stage wins as the race continues.
"The team controlled the whole race, and we set up a lead-out train," Wiebes said of the finish.
"After the last corner, especially Coryn put the speed so high that I only had to sprint for 150 metres, and that was enough.
"Tomorrow is a nice day for Coryn because she is better in the hills. There is another flat stage later, I will go for that. We have a strong team with the other girls as well and will go for more stage wins."
Team SD Worx maintained their stranglehold on the GC rankings with Anna van der Breggen still in top spot, now two minutes and 51 seconds ahead of Ashleigh Moolman-Pasio with Demi Vollering a further 12 seconds behind.
Most of the 120.1 kilometre flat stage comprised a four-lap circuit of the town of Carugate, and it was on the second lap that the first attack formed, spearheaded by Matilde Vitillo (BePink) with Noemi Lucrezia Eremita (Isolmant-Premac-Vittoria), Silvia Zanardi (BePink), Giorgia Vettorello (Top Girls Fassa Bortolo), Federica Piergiovanni (Valcar-Travel and Service) and Maria Novolodskaya (A.R Monex) giving chase.
The break stretched the gap out to as far as 2 minutes and 23 seconds, but were reeled in by the peloton with DSM at the fore 7 kilometres from the finish with only Novolodskaya attacking again before she was also caught at the four kilometre mark.
Trek-Segafredo and Canyon-SRAM both made their moves to the front inside the final 3 kilometres before DSM timed their charge to perfection with a kilometre left, allowing Wiebes to launch away from Norsgaard and claim the stage.
With wind likely to disturb the peloton in tomorrow's Stage 6 around the Lago di Como, van der Breggen voiced the need for her and her team to prepare accordingly if they're to maintain their hold on the maglia rosa.
"There can be a lot of wind, so there could be echelons," she said.
"We need to be at the front and can make the echelons, that can be nice, otherwise maybe it stays like today and the sprinters will keep it together for a stage victory. We need to see how much wind there is."
Watch the highlights from the Giro d'Italia Donne on SBS from 3:30pm weekends or 4pm weekdays (July 3-12) or available earlier via SBS On Demand and the Cycling Central website.