It will be only the fourth meeting of the two sides, and the Gunners have already triumphed over Los Rojiblanos 4-0 this season, Atleti's joint-heaviest defeat in the UCL.
Atleti are unbeaten against English teams at home
All four of those goals came in a 14-minute second-half blast from the North Londoners, who will undoubtedly be as keen to put on a similar performance at the Metropolitano to make the second leg at the Emirates Stadium a formality.
They'll be aware, of course, that the last North London club to visit the ground were sent back to the English capital with their tails between their legs.
Tottenham are one of six English teams to have played against Atleti at either the Metropolitano or Vicente Calderon and have never emerged with a victory.
Atleti have won three and drawn three against the Lilywhites, Man United, Man City, Liverpool, Chelsea and Leicester.
Two teams with most UCL games who haven't won the competition
Both Arsenal and Atleti have some synergy in the competition, too, given that they are the two teams that have played the most times in the European Cup/Champions League without winning it.
The Gunners' 223 fixtures are followed by Atleti's 190, and both will be hoping that if they progress to the final, they'll finally be able to break their duck against either Paris Saint-Germain or Bayern Munich.
It's the 16th time that English teams have had Spanish opposition in a European Cup/Champions League semi-final, and in the previous 15, nine of those from England have progressed to the final (60%), including in four of the last five seasons.
In the four knockout games that Mikel Arteta's side have contested in the competition so far in 2025/26, there have been just five goals scored, with Arsenal getting four of them.
History beckons for the Gunners
They'll certainly need to show all of those powers of resilience against a combative and competitive Atleti side, who have scored 17 in their knockout stage games, but conceded 11.
The Gunners did restrict the Rojiblancos to an xG of just 0.32 and one shot on target in the fixture earlier this season, both of which were Atleti's lowest return in a 25/26 UCL game, so the Premier League side does have it in them to play a different type of game if needs be.
If Arsenal do remain unbeaten after Wednesday night's fixture, they will have equalled their longest unbeaten run in the competition.
Currently having gone 12 UCL games without defeat, their 13-game unbeaten run between March 2005 and April 2006 formed the basis of their passage to the 2006 Champions League final against Barcelona, which remains their only UCL final appearance to date.
Gyokeres has to find his shooting boots
The North Londoners will hope that Viktor Gyokeres has his shooting boots on, with the Swedish international scoring half of his four UCL goals this season in that November game against Atleti.
However, in their four knockout matches, Gyokeres has only had six shots, and none of them has found the target.
Bukayo Saka remains vital for his team too, with Arsenal's xG rising from 1.8 per game without him to 2.3 with him in the side, and their goal average increasing from 1.5 to 2.6 per game.
Atleti, meanwhile, have collectively made 374 high-intensity pressures per game, which is the fifth-most of any team in the entirety of this season's competition, and of the semi-finalists, only Arsenal come close (281).
Alvarez and Griezmann key for Atleti
Their average of 7.1 defensive line-breaking passes per game is only bettered by PSG's 7.8, suggesting that they too can adopt a different, some might say less physical, style should it be required.
Indeed, Julian Alvarez has already scored the most goals ever in a single UCL campaign for Atleti (nine), whilst the evergreen Antoine Griezmann has been directly involved with 56 of Atleti's 231 Champions League goals (24.2%).
His 40 goals and 16 assists give him the highest percentage of a player in any team that's played over 100 games in the competition, and even pushes Lionel Messi (24.1%) into second place.
Both Griezmann and Alvarez could have their work cut out, however.
That's because in the 22 UCL games that David Raya, Gabriel and William Saliba have started together, Arsenal have kept 13 clean sheets (59%), and conceded just 11 goals (or 0.5 per match).
Whether this game is decided by pure artistry or sheer guts and determination, it's bound to be an absorbing watch.
