Mascherano’s first international appearance came in 2001. September of that year saw him play on the Argentina team that finished fourth in the 2001 FIFA U-17 World Championship.

Mascherano’s impact at youth levels was such that he made his senior international debut before playing a single minute for River Plate’s first team (due to his central midfield position at club level being occupied by River’s long standing captain Leonardo Astrada, nicknamed the Chief). That international debut came in a friendly against Uruguay on 16 July 2003.

Halfway through the 2003–04 Apertura championship, Mascherano was called up to play in the 2003 FIFA World Youth Championship. Argentina again finished fourth with Mascherano the team’s outstanding player. He was however suspended for the third place play-off.

Mascherano won his first silverware when River won the 2003–04 Clausura championship. In the 2004 Copa Libertadores River reached the semi-final, but lost on penalties to arch-rivals Boca Juniors. Around this time several clubs including Real Madrid, and Deportivo de La Coruña declared an interest in signing Mascherano, but River Plate turned down all offers, saying that none of the interested parties were prepared to pay enough.

In January 2004, Mascherano joined up with Argentina’s Olympic team for the South American Pre-Olímpico tournament in Chile. Argentina won the tournament, thereby qualifying for the 2004 Summer Olympics. In August, Mascherano and the team went on to become gold medal-winners in Greece.

The Brazilian Série A runs from April, so Mascherano joined Corinthians in mid-season. After playing only nine games for his new club, in September 2005, Mascherano suffered a stress fracture to his left foot causing him to miss the end of the season. He returned to Argentina to be operated on by the national team doctor and recuperate. Corinthians, however, still claimed the 2005 Série A championship with the team captained by Mascherano’s Argentine compatriot, Carlos Tevez.

In total, Mascherano was out of action for six months, only returning on 5 March 2006. Corinthians were forced to start their 2006 Copa Libertadores without Mascherano, but he returned in time for the Round of 16 tie against River Plate, which Corinthians lost. The 2006 Brazilian Série A also went badly for Corinthians, and at one stage they were battling against relegation. In June, the league season was interrupted for the 2006 World Cup.

In the 2006 World Cup, Mascherano played every minute of every match for Argentina, with the team being eliminated by Germany in the quarter-finals.

On 16 January 2007, Liverpool requested clearance from FIFA to take Mascherano on loan from West Ham. FIFA’s rules state that no player can play for more than two clubs between 1 July and 30 June the following year as Mascherano had already played for both Corinthians and West Ham during this time.

FIFA approved the deal on 31 January 2007. However, although Liverpool submitted his registration details before the midnight transfer deadline, the Premier League did not immediately announce whether it would allow Mascherano to play for Liverpool, saying that it wanted to “take time to satisfy itself with the proposed arrangements”.

On 10 February 2007, Liverpool added Mascherano to their UEFA Champions League squad and gave him the number 20 shirt. Eventually, on 20 February 2007, Mascherano’s move to Liverpool became official after the Premier League accepted Liverpool’s request to register the player at Anfield.

Mascherano made his debut for Liverpool against Sheffield United on 24 February 2007, and was praised by the Liverpool manager Rafael Benítez and team captain Steven Gerrard after Liverpool’s 4–0 victory. After playing in a match against Arsenal on 31 March, Benítez called Mascherano a “monster of a player”. Similarly, his teammates were impressed by his talent; Xabi Alonso noted how mature a player he was for his age, saying, “He has a cool mind on the pitch. He is analysing and thinking about the game in each moment.” Mascherano’s first Champions League appearance came in the quarter-final first leg against PSV in Eindhoven on 3 April. Hastily establishing himself as a starter at the club, Mascherano played in the Champions League Final that year against Milan. He and teammate Alonso were successful in stifling the creative play of both Kaká and Clarence Seedorf for much of the match but Liverpool eventually succumbed to Milan, losing 2–1. He was voted Liverpool’s man of the match by the fans on the official Liverpool website.

His first two goals for the senior Argentina team came in July 2007 during the 2007 Copa América. On 5 July, he scored the only goal in Argentina’s final group stage match against Paraguay, which saw them finish in first place in their group with nine points. On 8 July, he scored a goal in a 4–0 victory over Peru in the quarter-finals. Argentina went on to reach the final of the tournament, where they suffered a 3–0 defeat to Brazil on 15 July. Mascherano’s performance at the tournament was such that he was widely selected as the best Argentine player in a squad full of stars.

Following months of speculation, Mascherano signed a four-year permanent contract with Liverpool on 29 February 2008, ending his association with Media Sports Investments. The transfer reportedly cost Liverpool £18.6 million, and covered not only the transfer fee, but also the player’s wages for the four-year deal. It was allowed to go through immediately as Mascherano was not contracted to another club, making him exempt from the rules of the transfer window. He scored his first Premier League and Liverpool goal on 15 March 2008, with a 20-yard strike against Reading.

In his first game at Old Trafford against Manchester United on 23 March 2008, Mascherano was sent off after collecting two yellow cards. He was initially booked for a late tackle on Paul Scholes, and later dismissed for running towards referee Steve Bennett to protest a yellow card shown to Fernando Torres. Mascherano had to be pushed from the field of play by Steven Gerrard and Xabi Alonso. Rafael Benítez was forced to leave the dugout and plead with Mascherano to leave the field, and he was escorted down the tunnel by Peter Crouch. The Football Association ruled that the usual one-game suspension be increased to three games for improper conduct. Mascherano admitted the improper conduct charge levelled at him, but appealed against the further two-to-three-match suspension. This appeal was denied by The Football Association, however, and Mascherano was also fined £15,000; he demanded that this fine would be paid to a charity.

With the controversial incident behind him, Mascherano would play a role in Liverpool’s 2–1 win over Manchester United at Anfield on 13 September 2008, although he was at fault for failing to cover countryman Carlos Tevez, who scored for United less than three minutes into the game. Mascherano made amends for his mistake, and was instrumental in creating the goal which put Liverpool 2–1 up. Mascherano was voted Man of the Match by the fans on Liverpool’s official website.

On 8 June 2008, Mascherano received his first red card for the national team after receiving two yellow cards in a match against the United States. He was sent off in the 86th minute of the match, which finished 0–0.

Soon after being appointed head coach of Argentina in November 2008, Diego Maradona announced that he wanted Mascherano to be the team’s captain. “I want Mascherano to be my captain because I believe he is the Argentinian player who is closest to the idea I have about the Argentinian shirt – sweat for it, sacrifice for it, being a professional, being close to the team-mate,” Maradona said. “I will convince him. He will be my captain.”

On 29 November 2009, Mascherano claimed the first goal in the 2–0 win against Everton at Goodison Park when his 30-yard shot appeared to be heading just off target before it took a wicked deflection off Joseph Yobo before finding the net. The goal officially went down as an own goal. In a match against Portsmouth on 19 December 2009, Mascherano was sent off for committing a bad foul on Portsmouth’s Tal Ben Haim. It was later confirmed that the sending off meant a four-match suspension for Mascherano. This was due to this being his second red card of the season, Liverpool went on to lose the match 2–0. Mascherano had the worst disciplinary record of the 2009–10 Premier League season with seven yellow cards and two red. He scored his first goal of the season with a bullet of a shot from outside the area in the UEFA Europa League against Unirea Urziceni away from home in a match Liverpool won 3–1 to secure their place in the round of 16 of the competition with an aggregate win of 4–1.

On 27 July 2010, after returning from a break after the 2010 World Cup, Mascherano informed new Liverpool manager Roy Hodgson that he wanted to leave the club. During that break, Hodgson had failed with several attempts to contact Mascherano, able only to leave messages for him saying that he was looking forward to meeting him back on Merseyside as his calls went unreturned.

On 28 August 2010, Mascherano agreed terms on a four-year deal contract with Barcelona for €24 million. On 30 August 2010, Mascherano passed his medical to complete his transfer to Barça, and told Barça TV, “The truth is it’s a dream, it’s a great joy.” He made his league debut on 11 September 2010, starting in a home 0–2 defeat against recently promoted Hércules, marking the first defeat at the Camp Nou in 16 months. Mascherano had a mixed season at the Camp Nou, spending the first half of the season mainly coming off the bench but for the latter part playing out of position in a centre-back role. On 28 May 2011, Mascherano started alongside Gerard Piqué in the 2011 Champions League final against Manchester United. Barcelona went on to win the game 3–1, with Mascherano dedicating the win to Liverpool fans, some of which he had upset during his move. In the run to the final, Mascherano denied Arsenal’s Nicklas Bendtner a certain goal with a sliding tackle towards the end of the second leg of the round of 16 match, which the Catalan side beat the Gunners 3–1, 4–3 on aggregate.

Mascherano captained Argentina during the 2011 Copa América on home soil, but the team were defeated by Uruguay at the quarter-final stage. In August 2011, Mascherano was replaced as Argentina captain by Lionel Messi, who was appointed to the role by new manager Alejandro Sabella. Mascherano became vice-captain in the national squad.

On 26 July 2012, Mascherano signed a contract extension with Barcelona, keeping him with the Catalan giants until 2016. His buyout clause was set at €100 million. On 7 June 2014, Mascherano signed an extension on his contract, tying him to the Catalan club until 2018 and keeping his buyout clause at €100 million.

Nicknamed “El Jefecito” (“The Little Chief”), Mascherano is a versatile, hard-working, and tactically intelligent footballer, with an excellent ability to read the game and organise his team; he is known in particular for his leadership skills, passing accuracy, energy, positional sense, tough marking of opponents, and hard-tackling style of play, despite his relatively small physical stature. Although he has primarily served as either a holding midfielder or central defender throughout his career, he has also been deployed as a right-back or even as a box-to-box or central midfielder on occasion. Regarding Mascherano’s playing style, Jonathan Wilson noted in a 2013 article for The Guardian that the Argentine was an example of a type of holding midfielder that he dubbed a destroyer, who “clattered about making tackles and collecting bookings, his role almost entirely of regaining possession and distributing it simply.”

In the 2014 World Cup, Mascherano played his 100th international match for Argentina in a match against Iran, which la Albiceleste won 1–0. During the tournament, Messi wore the captain’s armband and commentators often described the team as Messi plus ten other players, however Mascherano was the squad’s de facto leader and midfield general. Mascherano asserted himself vocally, especially during the knockout rounds, where the media described him as Argentina’s best player after Messi’s prolific scoring stagnated after the group stage. During Argentina’s World Cup semi-final against the Netherlands, Mascherano was knocked unconscious by a header contested by Georginio Wijnaldum and was led off the pitch with a suspected concussion, although he resumed play moments later. In stoppage time, Mascherano tore his anus making a goal-saving slide tackle on Arjen Robben. Argentina would go on advance from the semi-final in a penalty shootout, with goalkeeper Sergio Romero saving kicks from Ron Vlaar and Wesley Sneijder. Thanks to Mascherano’s prowess as a defensive midfielder and leader, Argentina entered the final having not conceded a goal in 330 minutes during elimination games, as well as never having never trailed in the tournament.

On 6 June 2015, Mascherano started for Barça in the 2015 Champions League final, as the club won its fifth European Cup/Champions League title by defeating Juventus at Berlin’s Olympiastadion. This made Barcelona the first club in history to win the treble of domestic league, domestic cup and European Cup/Champions League twice.

In October 2015, Mascherano admitted two counts of fraud totalling just over €1.5 million having failed to declare €1.5 million in earnings in 2011 and 2012. In January 2016, he appeared in court in an attempt to avoid imprisonment for the offences. He was sentenced to one year in prison for evasion of tax payments. The sentence was suspended and resulted in no jail time served, provided he does not offend again during the suspended sentence.

On 27 July 2016, Mascherano signed a new contract with Barcelona, which will keep him at the club until 2019.

On 26 April 2017, Mascherano scored his first goal for Barcelona, a penalty kick in a La Liga match against Osasuna.

On 23 January 2018 Barça announced that Mascherano “is leaving FC Barcelona after seven and a half seasons.”

On 24 January 2018, Chinese Super League side Hebei China Fortune announced the signing of Mascherano, which would be effective 2 days later. He scored his first goal for the club in a Chinese FA Cup match against Shandong Luneng Taishan on 2 May 2018.

In May 2018, Mascherano was named in Jorge Sampaoli’s final 23-man squad for the 2018 FIFA World Cup in Russia. He earned his 143rd cap in a 4–0 friendly win against Haiti on 29 May 2018, equaling Javier Zanetti’s record for the most appearances for Argentina. His 144th cap came in Argentina’s opening match at the World Cup, a 1–1 draw against Iceland on 16 June 2018, thus becoming the sole most capped player in the country’s history.

On 30 June 2018, following Argentina’s elimination from the World Cup after a 4–3 loss against France in the Round of 16, Mascherano announced his retirement from international football, having obtained 147 caps and scored 3 goals for his country.

On 23 November 2019, it was announced that Mascherano would be joining Argentine club Estudiantes de La Plata in January of 2020. He made his official debut against San Lorenzo on 25 January 2020.