The 205km second stage from Bologna came down to a sprint finish in which the German national champion, making his Giro debut this year, had the power to hold off Italy's national champion.
Australian Caleb Ewan of Lotto-Soudal came in third behind the Deceuninck-QuickStep rider, with UAE Team Emirates' Fernando Gaviria fourth.
The bunch finish meant there was no change at the top of the general classification, in which Team Jumbo-Visma's Primoz Roglic holds the pink jersey with a 19-second advantage over Mitchelton-Scott's Simon Yates.
Two-time Giro winner Vincenzo Nibali of Bahrain-Merida is a further four seconds behind the Lancastrian in third place, with Tao Geoghegan Hart of Team Ineos in eighth place, 35 seconds off pink.
After Saturday's time trial, Sunday's stage set off from Bologna in damp conditions, with an eight-man breakaway quickly setting off up the road and building a lead of four-and-a-half minutes.
Bora-Hansgrohe did a huge amount of the work to chase them down on the approach to Fucecchio, with the catch made inside the last 10 kilometres.
The team looked to have blown their advantage inside the final 1,000 metres as others swamped them on the front, but Ackermann kept his cool and launched his attack right on cue.
"I'm so happy, this is my first chance to win a stage and we did it great," said Ackermann, selected by his team ahead of Irishman Sam Bennett, who won three stages of last year's Giro.
"I think that all the team is more motivated and it's good for the next three weeks.
"We saw with 250 metres to go that none of the sprinters had started the sprint. I decided to take my speed and go full gas and luckily it was enough."
The three-week race continues on Monday with a 220km stage from Vinci to Orbetello which again offers promise for the sprinters.
