Joshua Kimmich opened the scoring for Germany from the penalty area after 10 minutes, before Ilkay Gundogan added a second from the penalty spot just before half-time.
Thomas Müller made it 3-0 five minutes into the second half, before two goals in under two minutes from Timo Werner – the second of which came after a confusion in the Italian defense – put the game further out of reach for Italy.
Wilfried Gnonto pulled one back from close range as Manuel Neuer’s save was pushed in his way – the 18-year-old’s first goal for Italy – while Alessandro Bastoni’s header from a corner turned out to be a late consolation goal.
The result means that after 13 games, Flick has yet to suffer a defeat as Germany head coach, with his side taking a historic first win against Italy in their 11th meeting.
“We are angry, there are no excuses tonight,” said goalkeeper Gianluigi Donnarumma.
“We have to look each other in the eye and start over to show that this is not the real Italy. We lacked everything tonight.”
It was also a night to forget for England, Italy’s opponent in last year’s Euro 2020 final, after a 4-0 defeat to Hungary in Molineux – Hungary’s first away win against England since 1953.
Despite the Three Lions dominating the opening stages of the match, Hungary took the lead when Roland Sallai scored from a free kick in the penalty area.
Reece James headed the ball off the line to prevent Hungary from scoring another goal later in the first half, but Sallai stunned the home side again in the 70th minute when he brought in his second.
Things went from bad to worse for England as Ádám Nagy knocked down third place in Hungary, John Stones was sent off for a second yellow card and Dániel Gazdag completed the defeat.
The defeat marked England’s second consecutive defeat against Hungary and the fourth game without a win in the Nations League this season.
“I have chosen a very young team, that is my responsibility,” said head coach Gareth Southgate.
“I did not find the balance in the two games against Hungary. After the first goal, the fear crept in a bit and we could not recover from that.”
The next round of Group A3 matches will take place on September 23 with Italy hosting England and Germany hosting Hungary.