It has been six years since the two coaches last met in Europe's premier club competition, when Los Rojiblancos took on Bayern Munich in the competition's semi-finals in the 2015/16 campaign.
While encounters between the two managers have been few and far between, Simeone has been a familiar face in England this season as he and his men faced Liverpool in the group stage, and lost both fixtures, while he had better success against Manchester United, a side he helped eliminate in the round of 16.
Spain's LaLiga: 2. Carlo Ancelotti (Real Madrid) - €910 000 a month
Spain's LaLiga: 1. Diego Simeone (Atletico Madrid) - €3.33 million a month
Spain's LaLiga: 3. Marcelino (Athletic Bilbao) - €500 000 a month
England's Premier League: 2. Jurgen Klopp (Liverpool) - €1.49 million a month
England's Premier League: 3. Antonio Conte (Tottenham Hotspur) - €1.49 million a month
France's Ligue 1: 2. Jorge Sampaoli (Olympique Marseille) - €330 000 a month
Germany's Bundesliga: 3. Marco Rose (Borussia Dortmund) - €375 000 a month
France's Ligue 1: 1. Mauricio Pochettino (Paris Saint-Germain) - €1.1 million a month
England's Premier League: 1. Pep Guardiola (Manchester City) - €1.89 million a month
France's Ligue 1: 3. Christophe Galtier (OGC Nice) - €330 000 a month
Italy's Serie A: 2. Jose Mourinho (AS Roma) - €770 000 a month
Italy's Serie A: 1. Massimiliano Allegri (Juventus) - €1.17 million a month
Germany's Bundesliga: 2. Gerardo Seoane (Bayer Leverkusen) - €416 000 a month
Germany's Bundesliga: 1. Julian Nagelsmann (Bayern Munich) - €666 000 a month
Italy's Serie A: 3. Simone Inzaghi (Inter Milan) - €620 000 a month
The Argentine will now come up against Guardiola in the quarter-finals of the continental competition, with the two bosses having clashed only once during the Spaniard's days as FC Barcelona manager.
The 51-year-old has now shared his thoughts on the City tactician ahead of that tie.
"In the teams where I was, I never had the chance to have Xavi, [Sergio] Busquets, [Gerard] Pique, [Andres] Iniesta, and [Lionel] Messi... all young," Simeone said, according to Movistar Plus.
"So beyond Guardiola's great talent, he was lucky to be accompanied by extraordinary players."
10. Tottenham Hotspur - €406.2 million
9. Juventus - €433.5 million
8. Chelsea - €493.1 million
7. Liverpool - €550.4 million
6. Paris Saint-Germain - €556.2 million
5. Manchester United - €558 million
4. FC Barcelona - €582.1 million
3. Bayern Munich - €611.4 million
2. Real Madrid - €640.7 million
1. Manchester City - €644.9 million