Evenepoel put 43 seconds on his pre-race rival, Primoz Roglic (33), a big margin given the length of the first stage of the race. Hour record holder and former world time-trial champion, Filippo Ganna (27), finished second on the day with a time of 21 minutes and 40 seconds. In third was Tao Geohegan Hart (28) of Ineos Grenadiers, 40 seconds behind Evenepoel.
"I am super happy, it is the best result we could have expected from today," said Evenepoel after the stage.
"I think it is not really focussing on the gap to him (Roglic), I just wanted to go as fast as possible, this is the first mission accomplished and now we have to focus on the next stages.
Speaking about taking his first leader's jersey, he added: "I want to enjoy this, it is a nice way to come back to the Giro.
Of the earlier starters, the first notable leader was Mads Pedersen (27), who is looking to complete the set of grand tour stage wins at this year’s Giro, but his time didn’t last long as UAE Team Emirates’ Brandon McNulty (25) took over the hot seat with a time of 22 minutes and six seconds, storming up the final two-kilometre climb with a time of three minutes and 52 seconds.
Times were noticeably quick on the Adriatic coast with a tailwind blowing the riders along the route.
It was worse news for Hugh Carthy (28) - the leader for EF Education First EasyPost - who lost nearly two minutes on the best time of the day.
Jay Vine (27) - teammate of McNulty - was the next to set the fastest time as he looks to see what he can do in the overall over three weeks for the first time. The Australian national TT champion has been out with injury for much of 2023, but looked in great shape in the opening stage, setting a very good time of 22:04.
That would not last long as the 2020 winner of the Giro, Tao Geohegan Hart went six seconds quicker. His teammate and co-leader of the race, Geraint Thomas, would stop the clock at 22:13. Joao Almeida would beat Geohegan Hart’s time by 10 seconds.
But the big hitters were still to come as Evenepoel, Roglic, Ganna and Kung - all looking to take the first pink jersey of the race - set off.
They would go through the first time check after nine kilometres one after another and Evenepoel set a blistering time, 20 seconds up on the fastest time set.
Roglic would go through the same point an eye-catching 26 seconds down, whilst time-trial specialists Ganna and Stefan Kung would be 12 and 22 seconds adrift respectively.
That gap would only extend with the Belgian TT champion finishing 29 seconds ahead of Almeida in a warning of his form to the rest of the field.
Roglic came in soon after, finishing with a time of 22:01, a huge deficit on his race rival Evenepoel. Kung finished in the same time and nor he, or Ganna, could do anything to stop the Belgian from donning the first Maglia Rosa of the race.
The first road stage of the race gets under way on Sunday, a likely sprint stage, with a 202-kilometre ride from Teramo to San Salvo.