The Manchester United shot stopper pulled off a string of saves to keep his side in the game but Giorgio Chiellini's 33rd-minute goal and Graziano Pelle's late goal deservedly handed the Italians victory and a quarter-final encounter with Germany.
Four years on from losing to Spain 4-0 in the last European Championship final, Italy burst out of the blocks, forcing de Gea into two world class saves early on.
The first came from a Pelle header before de Gea then turned Emanuele Giaccherini's overhead kick onto the post – although referee Cuneyt Cakir penalised the Italy man for dangerous play for the latter.
Marco Parolo headed wide on 25 minutes before Sergio Ramos also shanked wide of his own goal as Italy continued their high tempo approach.
And the breakthrough deservedly came on 33 minutes through Chiellini from close range.
Ramos conceded a freekick on the edge of his box following a foul on Pelle, Eder fired it in low and de Gea could only parry with Giaccherini looking to poke home before Chiellini then got the final touch.
A second goal almost arrived on the stroke of half-time but de Gea flung himself high to his left to keep out a curling Giaccherini effort that looked certain to find the top corner.
After being outplayed in the first half, Spain had the first real chance after the break but Alvaro Morata could only direct his header straight at Gianluigi Buffon.
De Gea then again came to the rescue for his country on 56 minutes when he raced out to deny Eder who had been played clean through following Pelle's flick.
With just a goal separating the two sides, Spain were not out of it and Lucas Vazquez struck the post from an offside position before Buffon had to deny Andres Iniesta and Gerard Pique from distance.
With time almost up, Buffon equalled his opposite number's heroics by tipping away Pique's volley and just moments later the game was up when Pelle volleyed home substitute Matteo Darmian's cross.
STATS
Italy 2
Chiellini 33
Pelle 90
Spain 0
Referee: Cuneyt Cakir 6/10
Match rating: 4/5
Star man: David de Gea (9/10)
Italy: (3-5-2): Buffon 7, Chiellini 7, Bonucci 6, Baragli 7, De Sciglio 8, Giaccherini 8, De Rossi 6 (Motta 53 x), Parolo 6, Florenzi 8 (Darmian 84 7), Eder 7 (Insigne 81 6), Pelle 9
Spain: (4-3-3) De Gea 9, Alba 5, Ramos 4, Pique 5, Juanfran 5, Iniesta 7, Busquets 5, Fabregas 6, Nolito 4 (Aduriz 45 4) (Pedro 80 6), Morata 6 (Lucas 70 6), Silva 6
Sportsbeat 2016
Source: Sportsbeat
