Italy saw their world record unbeaten run come to an end after 37 games and three years, but it was also their first competitive defeat in Milan since 1925.
The Azzurri knew their streak had to reach a conclusion sometime and it happened in the Nations League semi-final against Spain, a 2-1 result.
They were already a goal down when Leonardo Bonucci was sent off for a second bookable offence, making the comeback improbable.
Roberto Mancini oversaw a run of 28 victories and nine draws ahead of this defeat, a new all-time world record for international teams.
This beat the 36 set by Brazil from 1993-96 and 35 by Spain in 2007-09.
Italy had not tasted defeat since September 10, 2018, a 1-0 loss to Portugal.
The record run began almost a full three years before it ended, with a 1-1 friendly draw against Ukraine on October 10, 2018.
It was also their first defeat in the city of Milan since 1925, although San Siro has hardly been kind to the Nazionale recently.
The last victory in this arena was nine years ago, in October 2012 against Denmark, followed by five consecutive draws and this defeat.