In his club career that started in 1987, Simeone played for Vélez Sarsfield, Pisa, Sevilla, Atlético Madrid, Internazionale, Lazio and Racing; he won a domestic double with Atlético Madrid in 1996, and the UEFA Cup with Inter in 1998, also winning another domestic double with Lazio in 2000, as well as the 1999 UEFA Super Cup and the 2000 Supercoppa Italiana. Simeone was capped over 100 times for the Argentina national football 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; he also won the FIFA Confederations Cup in 1992, and a silver medal at the 1996 Summer Olympic games.
As a manager, Simeone has coached Racing, Estudiantes, River Plate, San Lorenzo, and Catania, before joining Atlético Madrid in 2011. He won the Argentine Primera División both with Estudiantes and River Plate, and has won five titles since joining Atletico Madrid, including the La Liga title, the Copa del Rey, and the UEFA Europa League, also reaching two UEFA Champions League finals with the club.
When Simeone was 14, his youth coach Victorio Spinetto nicknamed him Cholo, as his energetic play reminded him of former Boca Juniors player and Argentine international Carmelo Simeone (no relation) who possessed the nickname.
After starting his career with Vélez Sarsfield, Simeone moved to Italian Serie A club Pisa in 1990. The club was relegated in his first season and, after it failed to gain promotion the following year, Simeone was sold to Sevilla in the Spanish Primera División. Simeone played two seasons in Seville, after which he was signed by Atlético Madrid. At Atlético, he was part of the team which won the double of the Liga title and Copa del Rey during the 1995–96 season.
In 1997, Simeone returned to Serie A with Internazionale and played two full seasons, winning the 1997–98 UEFA Cup in a side spearheaded by Ronaldo up front. In 1999, Simeone joined fellow Argentines Néstor Sensini, Matías Almeyda, Hernán Crespo and Juan Sebastián Verón at Sven-Göran Eriksson's Lazio. The side had gone close to the Scudetto in the season before Simeone's arrival and he helped deliver the championship after a season, where Juventus led the standings by two points going into the last day. A Juve loss at rainy Perugia coupled with Lazio's comfortable home win over Reggina at the Stadio Olimpico ensured Simeone's first Serie A title. After winning the double in Spain, he would then add the Italian double as Lazio edged out Inter to claim the 1999–2000 Coppa Italia.
He went on to play three more seasons in Rome, which included more last day drama as a Simeone goal against former club Inter on the last day of the 2001–02 campaign effectively ruined his old employers' title dream.
Simeone returned to Atlético Madrid in 2003, spending his next two seasons there. In total, he played in 165 matches for Atlético, scoring 31 goals. In 2005, he left Europe to finish his playing career in Argentina with Racing.
In 1992, Simeone represented Argentina U23 at the 1992 CONMEBOL Pre-Olympic Tournament in Paraguay, which saw Argentina fail to qualify for the 1992 Summer Olympics.
For the Argentine senior team, Simeone amassed 106 caps, the first coming in 1988.
Simeone won the 1991 and 1993 editions of the Copa América with Argentina. He played in the 1994, 1998 and 2002 FIFA World Cups. He was a member of the team that won the silver medal at the 1996 Summer Olympics in Atlanta, Georgia, as one of the three over-23 players allowed per squad. As a midfielder, Simeone scored 11 goals for his country, including one in the final of the 1992 King Fahd Cup.
During the 1998 World Cup, England's David Beckham was sent off for kicking Simeone in retaliation for a foul (see also Argentina and England football rivalry). Simeone later said that he simulated the injury from the kick in order to get Beckham sent off. Sports Illustrated was critical of the Argentinian's theatrics in that incident, stating that Simeone first delivered a "heavy-handed challenge" on Beckham and then "fell like a ton of bricks" when Beckham retaliated. In the following match, against the Netherlands, Simeone was injured by a tackle from Arthur Numan during his team's defeat. In the 2002 World Cup, his last, Argentina was eliminated in the group stage, which included a 1–0 loss to England where Beckham converted a penalty.
Simeone said that he was "embarrassed" at having surpassed Diego Maradona as Argentina's most capped player (he has since been surpassed by Roberto Ayala, Javier Mascherano, Javier Zanetti, and Lionel Messi).
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, also having a penchant for scoring several goals himself; this enabled him to play anywhere in midfield throughout his career, although he was usually deployed in the centre in a box-to-box or defensive midfield role. A talented yet combative player, he was primarily known for his leadership, tactical versatility, intelligence, strength, and stamina, although he was also praised by pundits for his technique, vision and passing range. Simeone once described his style as "holding a knife between his teeth." His main inspirations as a player were Brazilian midfielder Paulo Roberto Falcão and German midfielder Lothar Matthäus.
Simeone ended his playing career for Racing, playing his last match on 17 February 2006, and then became manager for the same team. After a rough start, the team made an impressive finish in the 2006 Clausura. When a new club president was elected, Simeone left Racing in May 2006 and was replaced by Reinaldo Merlo.
On 18 May, he became head coach of Estudiantes de La Plata 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. In an October 2006 poll in the sports daily Olé, Simeone was voted as the best manager in the Argentine league. He was also praised as a "born manager" by former Argentine international Roberto Perfumo. Simeone left Estudiantes after the end of the 2007 Apertura, where Estudiantes was not a contender after a poor start, but had a strong finish of nine games without defeat. On 15 December 2007, Simeone was unveiled as the new River Plate coach, succeeding Daniel Passarella. The contract was reported to be a year long, starting on 3 January 2008. 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. On 7 November 2008, Simeone announced his resignation as coach of River Plate after their elimination at the quarter-final stage of Copa Sudamericana 2008 by the Mexican team Chivas and a poor run of form of 11 domestic games without a win, which left them bottom of the Primera División Argentina with only six games remaining. On 15 April 2009, Simeone joined San Lorenzo to replace Miguel Ángel Russo, following the club's exit in the first round of Copa Libertadores 2009. On 3 April 2010, the Simeone quit San Lorenzo due to poor results and mounting criticism.
On 19 January 2011, Simeone flew to Sicily to join Serie A side, Catania, replacing Marco Giampaolo, who left the club just hours earlier. On 1 June 2011, he left his post after helping Catania stave off relegation. 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 prior week.
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. His first season ended with the team winning the UEFA Europa League by beating Athletic Bilbao 3–0 in the final in Bucharest.
On 31 August 2012, he won the UEFA Super Cup after beating Chelsea 4–1 at the Stade Louis II in Monaco. On 17 May 2013, he won the Copa del Rey with Atlético beating rivals Real Madrid 2–1 at the Santiago Bernabéu. Simeone also led the team to a third-place finish in 2012–13 La Liga.
Atlético began the 2013–14 season with a similar squad to their prior season, despite selling star player Radamel Falcao to Monaco for a reported €60 million fee, and acquiring David Villa from Barcelona on a free transfer. While the season began with defeat to Barça in the 2013 Supercopa de España, the team recorded eight-straight victories in La Liga, the best league start in its 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. Atlético finished the first half of the season first place in La Liga, level on points as Barcelona, with 47. In the last round of the season, on 17 May, Atlético needed at least a draw in the Camp Nou against Barcelona to be crowned champions for the first time since 1996, while a loss would give the title to Barcelona. A Diego Godín header from a corner kick in the 48th minute gave Atlético an equaliser and the draw that they needed to win their tenth league title, and first since 1996 when Simeone himself was an Atlético player. Simeone became the second Argentine manager after Helenio Herrera to hand Atlético a Spanish championship, and the second manager after Luis Aragonés to win it both as a player and as a coach of the team. Under Simeone, Atlético collected 90 points in La Liga, surpassing its 1996 record of 87, making the 2013–14 season the most successful in the club's history.
Atlético finished top of their Champions League group and qualified for the quarter-finals with a 5–1 aggregate win over Milan in the last 16. This was the first time that they had reached the Champions League quarter-finals since 1996–97, when Simeone played for the team. In the quarter-finals, Atlético played against fellow La Liga team Barcelona, and won 2–1 on aggregate from Simeone's tactic of cutting the swift-passing midfield of Barcelona in two, thus denying them space and isolating Xavi and Andrés Iniesta from forwards Lionel Messi and Neymar. In the semi-finals, Atlético beat 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 the club's history, the first being in 1974. Atlético was the only undefeated team in the Champions League before the final, recording nine wins and three draws, and had the best defence in the competition, conceding only six goals in 12 matches.
In the final on 24 May, Atlético faced city rivals Real Madrid in the Estádio da Luz in Lisbon. Despite leading from Diego Godín's header Atlético conceded a late equaliser in the 93rd minute of the match. The goal hampered Atlético's morale and the team ended up losing 4–1 after extra time, with Simeone losing the opportunity to be the third Argentine coach to win the Champions League, after Luis Carniglia and Helenio Herrera. After the final goal, Real Madrid's Raphaël Varane kicked the ball towards Simeone, causing him to run onto the pitch in anger. He was sent to the stands and Varane booked for the incident. Reflecting, Simeone said, "I also made a mistake with my reaction. He's a young guy with a bright future." Simeone also admitted a mistake in selecting striker Diego Costa to start the match, as he had been recently injured and went off after eight minutes.
On 5 September 2017, Simeone extended his contract with Atlético for two more years, until June 2020.As of 23 September 2017
Atlético Madrid (2)
La Liga (1): 1995–96
Copa del Rey (1): 1995–96
UEFA Cup (1): 1997–98
Serie A (1): 1999–2000
Coppa Italia (1): 1999–2000
Supercoppa Italiana (1): 2000
UEFA Super Cup (1): 1999
FIFA Confederations Cup (1): 1992
Copa América (2): 1991, 1993
Olympic Silver Medal: 1996
Trofeo EFE (1): 1995–96
Estudiantes de La Plata (1)
Argentine Primera División (1): Torneo Apertura 2006
River Plate (1)
Argentine Primera División (1): Torneo Clausura 2008
Atlético Madrid (5)
La Liga (1): 2013–14
Copa del Rey (1): 2012–13
Supercopa de España (1): 2014
UEFA Europa League (1): 2011–12
UEFA Super Cup (1): 2012
UEFA Champions League Runner-up (2): 2013–14, 2015–16
La Liga Manager of the Month (2): October 2013, November 2015
La Liga Coach of the Year (3): 2012–13, 2013–14, 2015–16
Miguel Muñoz Trophy (2): 2013–14, 2015–16
IFFHS World's Best Club Coach (1): 2016
European Coach of the Season: 2011/12
Simeone's son Giovanni is a professional football player, who currently plays for Italian club Fiorentina, in Serie A. His third son, Giuliano, was seen as a ball-boy for Atlético Madrid.