Simeone was capped over 100 times for the Argentina national team and represented the country at the 1994, 1998, and 2002 FIFA World Cups, and in four editions of the Copa América, winning the tournament in 1991 and 1993.

[10] In 1997, Simeone returned to Serie A with Inter Milan,[11] and played two full seasons, winning the 1997–98 UEFA Cup in a side spearheaded by Ronaldo up front.

[12] In 1999, Simeone joined fellow Argentines Néstor Sensini, Matías Almeyda and Juan Sebastián Verón at Sven-Göran Eriksson's Lazio.

A Juve loss at rainy Perugia coupled with Lazio's comfortable 3–0 home win over Reggina at the Stadio Olimpico ensured Simeone's first Serie A title.

[28] During the round of 16 of the 1998 World Cup, England's David Beckham was sent off for kicking Simeone in retaliation for a foul (see also Argentina–England football rivalry); Argentina won the match on penalties.

[20] Simeone was regarded as a tenacious, versatile, hard-working and complete two-way midfielder who was mobile, good in the air, and capable both of winning balls and starting attacking plays, while also having a penchant for scoring several goals himself.

[39] A talented yet combative player, he was primarily known for his leadership, tactical versatility, intelligence, strength and stamina,[40] although he was also praised by pundits for his technique, vision and passing range.

On 18 May, Simeone became head coach of Estudiantes and soon led them to their first league title in 23 years after defeating Boca Juniors 2–1 in a final match played on 13 December 2006.

[44] After an early elimination in the Copa Libertadores, losing to San Lorenzo in the second round, Simeone and River Plate went on to win the 2008 Clausura championship after beating Olimpo 2–1 in the Monumental.

[49] On 19 January 2011, Simeone flew to Sicily to join Serie A side Catania, replacing Marco Giampaolo, who left the club just hours earlier.

[52] On 21 June 2011, Simeone was named as the new coach of Racing Club for a second spell in charge, replacing Miguel Ángel Russo, who had resigned the week prior.

[53] On 23 December 2011, Simeone was unveiled as the new Atlético Madrid coach, succeeding Gregorio Manzano, who had been dismissed the day before following defeat to third-tier Albacete in the Copa del Rey.

In the domestic league, the team made an impressive start to the season, finishing the first half in second place, behind only Barcelona and above city rivals Real Madrid.

[55] While the season began with a defeat to Barça in the 2013 Supercopa de España, the team recorded eight-straight victories in La Liga, the best league start in club history.

This included a 1–0 away win at the Santiago Bernabéu against Real Madrid, making Simeone the first Atlético manager since Claudio Ranieri in 1999 to record a league victory there.

In the semi-finals, Atlético defeated José Mourinho's Chelsea 3–1 at Stamford Bridge following a goalless draw at home to reach the Champions League final for only the second time in club history, the first being in 1974.

[57] Atlético was the only undefeated team in the Champions League prior to the final, recording nine wins and three draws, and had the best defence in the competition, conceding only 6 goals in 12 matches.

In response, Atlético acquired striker Mario Mandžukić from Bayern Munich, goalkeeper Jan Oblak from Benfica and forwards Antoine Griezmann from Real Sociedad and Ángel Correa from San Lorenzo, and recovered young midfielder Saúl who was on loan at Rayo Vallecano.

The season started with Atlético defeating city rivals Real Madrid for the Spanish Super Cup in August and repeating the previous year's victory in the Bernabéu for the league in September.

Before the start of the 2015–16 season, Filipe Luís returned from Chelsea with the team also acquiring Montenegrin defender Stefan Savić and Belgian midfielder Yannick Carrasco.

Atlético had defeated PSV on penalties during the round of 16, beat defending champions Barcelona 3–2 on aggregate and favourites Bayern Munich 2–2, going through on away goals, setting up a repeat of the 2014 final again facing Real Madrid.

In the summer of 2016, Atlético purchased forward Kevin Gameiro from Sevilla, midfielder Nicolás Gaitán from Benfica, and defender Šime Vrsaljko from Sassuolo.

[74] After a 4–0 away defeat to Bayern Munich and many injuries to key players in November 2020, Simeone modified the formation of his squad by introducing a three-man defence for the first time in his tenure coaching Atlético.

Simeone has listed his coaching influences being Marcelo Bielsa, Sven-Göran Eriksson, Alfio Basile, Victorio Spinetto, Luigi Simoni, Carlos Bilardo and Radomir Antić.

[86][87] In the short time he managed Italian side Catania in 2011, he switched between a 4–2–3–1 and a 4–3–1–2 in order to bring out the best from playmaker Adrián Ricchiuti while employing many of the counter-attacking features that would later become his trademark at Atlético.

Ricchiuti was tasked with linking the midfield and attack and creating chances for whichever of Maxi López, Gonzalo Bergessio and Francesco Lodi were selected up front.

In the 2015–16 UEFA Champions League semi-final against Bayern in Munich, with his team down 1–0 after 45 minutes, he moved Saúl Ñíguez from the right wing to a holding midfielder position, changing the 4–4–2 to a 4–1–4–1 formation with Yannick Carrasco and Antoine Griezmann on the flanks.

"[92] During a leg in the 2017–18 UEFA Europa League semi-final against Arsenal at the Emirates, Atlético were playing without key players Diego Costa, Juanfran, Filipe Luís and Vitolo, and in the 10th minute, Šime Vrsaljko was sent off with a red card, followed by Simeone being also sent off.

Despite playing with ten men, without their manager at the bench, with most players in makeshift positions, and enjoying only 24% of ball possession, the team lost neither its shape nor its composure, eventually holding out to a 1–1 draw that was enough for them to progress to the final.

[93] "Simeone taught us to enjoy suffering," Arda Turan said in 2015, supporting this feeling that the Argentinean coach is a man who takes the best things out of bad situations.