When: Tuesday, July 6, 8pm BST
How to watch: BBC One
This is not the first time these two nations have clashed on the big stage. In fact, this is a rivalry that goes back a century.
Since their first game - 101 years ago - this fixture has produced many memorable moments.
More history will be made on Tuesday at Wembley and, according to the bookmakers, it will be a far more memorable night for the Italians.
Before the start of the tournament, Italy were regarded as the dark horses. However, their consistently impressive performances have forced the bookies to change their perceptions and accept the fact that Gli Azzurri are serious title contenders.
Last three matches
Spain 3-0 Italy (World Cup Qualifiers - September 2, 2017)
A packed Santiago Bernabeu watched on as Spain dismantled Italy in their World Cup qualifying game.
Isco's first-half brace gave the Spaniards a two-goal advantage at the break and Alvaro Morata added a third in the 77th minute to seal an impressive win in Madrid.
Italy 1-1 Spain (World Cup Qualifiers - October 6, 2016)
A year earlier, Italy were able to produce a far more competitive performance as they held Spain to a 1-1 draw in Turin.
Vitolo opened the scoring for the visitors in the early stages of the second half.
However, Italy came back strongly and found an equaliser courtesy of a Daniele De Rossi penalty.
Italy 2-0 Spain (Euro 2016 - June 27, 2016)
The last meeting between Italy and Spain at a major tournament took place at the round-of-16 stage of Euro 2016.
The Spaniards entered the competition as the defending champions. However, a 2-0 loss in Saint-Denis saw them eliminated.
Giorgio Chiellini and Graziano Pelle scored the goals as Italy progressed to the quarter-finals.
Last 10 head-to-heads
Italy wins: 2
Spain wins: 5
Italy goals: 7
Spain goals: 12
Thirty-two not out
Following their 2-1 win over Belgium in the quarter-final, Italy's unbeaten run currently stands at 32 matches.
What's more, Mancini's men have won 13 straight games and conceded just two goals in that time.
The former Man City manager has got his side playing highly technical, possession-based soccer. The foundation of this system is the midfield trio of Marco Verratti, Nicolo Barella and Jorginho.
That, coupled with the experienced centre-back pairing of Leonardo Bonucci and Giorgio Chiellini, has made the Italians an incredibly tough side to score against, never mind beat.
Considering their strengths, one bet which stands out is the 11/2 offer on the Italians to score over 1.5 goals, take over 4.5 corners and receive over 1.5 cards.
This exact bet landed during Italy's quarter-final win over Belgium.
Italy's Euro 2020 results…
Masters of the semi-final
As one of the most successful sides in international soccer, Spain have been in their fair share of major tournaments. Yet despite this, they have never lost a semi-final.
In truth, it's been a while since Spain last reached the last-four stage. But then again, last time they did so, Spain ended up going all the way at Euro 2012.
There are, however, a lot of differences between the current crop of players and the ones who defended their European crown in Kyiv.
While that team was at the tailend of a golden generation, today's squad seems to be at the beginning of a new frontier.
The likes of Unai Simon, Pau Torres, Rodri, Pedri, Ferran Torres and Mikel Oyarzabal are all aged 25 or younger. Clearly, the future looks promising for Luis Enrique's side.
However, while the potential is undeniable, there are question marks about this team's current title-winning credentials. More specifically, their defensive vulnerabilities.
This is a side that has conceded five goals at Euro 2020 - three against Croatia alone in the round-of-16 stage.
With that in mind, a simple 10/11 bet in the both teams to score market certainly makes a lot of sense.
Spain have scored 11 goals over their last three games and their ability to put the ball into the back of the net is there for all to see. Question is, are they able to keep the Italians out?
Spain's Euro 2020 results…
Two men who haven't made the goalscorer list at Euro 2020 are the centre-back pairing of Bonucci and Chiellini - that's despite having two efforts chalked off by VAR earlier in the tournament.
Considering both were on the pitch during Italy's 4-0 defeat to Spain in the Euro 2012 final, it would be some story for them to score in Tuesday's semi-final.
At the price of 11/1 and 14/1 respectively, the duo offer great value to score anytime. They've already come close to opening their accounts at these championships and with the Italians placing a great deal of importance on their set-pieces, the duo could yet have more opportunities.
From a Spanish perspective, the man to back is Alvaro Morata. The Juventus forward is under a lot of scrutiny, but he's got two goals at the tournament and has recently netted against the Italians too.
The 9/4 offer on Morata to score anytime also offers decent value.