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 in 2003 and played two more seasons before leaving Europe to return to Argentina with Racing.
For the Argentine 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 2002World 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 Confederations 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 admitted to simulating 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 once described his style as "holding a knife between his teeth". Simeone admitted to being "embarrassed" at having surpassed Diego Maradona as Argentina's most capped player (he has since been surpassed by Roberto Ayala and Javier Zanetti).
Simeone ended his playing career for Racing, playing his last match on February 17, 2006, and then became manager for the same team. After a rough start, the team made an impressive finish in the 2006 Clausura. When ownership of the club changed hands, Simeone left Racing in May 2006 and was replaced with Reinaldo Merlo. On May 18, 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 December 13, 2006. In an October 2006 poll in the sports daily Ole, 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 bad start, but had a strong finish of nine lossless games. On December 15, 2007 Simeone was unveiled as the new River Plate coach, succeeding Daniel Passarella. The contract was reported to be a year long, starting on January 3, 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 November 7, 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 April 15, 2009 Simeone joined San Lorenzo to replace Miguel Angel Russo, following the club's exit in the first round of Copa Libertadores 2009. On April 3, 2010 the coach quit San Lorenzo due poor results and mounting criticism. On January 19, 2011, Simeone flew to Sicily to join Serie A side, Catania, replacing Marco Giampaolo who left the club just hours earlier. On June 1, 2011, he left his post after helping Catania stave off relegation. On June 21, 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 December 23, 2011, Simeone was unveiled as the new Atlético Madrid coach, succeeding Gregorio Manzano. On May 9, 2012, Simeone won the UEFA Europa League with Atlético Madrid beating Athletic Bilbao 3–0. On August 31, 2012 he won UEFA Super Cup with same team beating Chelsea 4–1, earning his first two European trophies. On May 17, 2013, he won the Copa del Rey with Atletico Madrid beating Real Madrid 2-1. Simeone led the team to a 3rd place finish in 2012-13 La Liga, the club's best finish in the competition since 1996. In 2014, Simeone led Atletico to their first Champions League semi final in over 40 years, defeating Barcelona 2-1 on aggregate.