Italy have failed to qualify for the World Cup for the first time since 1958 after a goalless second-leg draw against Sweden on Monday led to a 1-0 aggregate defeat.
Gian Piero Ventura's side dominated possession at the San Siro but could not find a way past Sweden goalkeeper Robin Olsen, who saved from Ciro Immobile and Alessandro Florenzi at the end of the first half and then denied Stephan El Shaarawy late in the game.
Sweden offered little in attack but held on to secure their first World Cup appearance since 2006.
There were tears among the Italian players at the final whistle as defeat looks set to mark a changing of the guard, with several experienced players now unlikely to play at another World Cup.
Goalkeeper Gianluigi Buffon - after winning his 175th cap - is set to retire at the end of the season while Daniele De Rossi, Giorgio Chiellini and Andrea Barzagli will all be in their late 30s in 2022.
Head coach Ventura also faces a battle to keep his job after Italy again failed to break down Sweden over 90 minutes, despite showing much more attacking intent than they did in the first leg.
The game started in scrappy fashion, with penalty appeals waved away at both ends and Jakob Johansson, scorer of the only goal of the tie, forced off with injury.
The first clear chance only arrived in the 27th minute when Immobile's pass across the face of goal spilled out to Antonio Candreva and he blazed over from 12 yards out.
Sweden were denied a penalty when the ball struck Matteo Darmian's arm, but had to hold on late in the first half as Italy applied sustained pressure.
Immobile saw a shot half-saved by Olsen and then cleared off the line by Andreas Granqvist before Florenzi was denied by Olsen after cutting into the box from the left.