He started playing for the side, becoming the youngest player to debut in the first division at 15 years and 35 days (on 5 July 2003 against Club Atlético San Lorenzo de Almagro), when Independiente's coach, Oscar Ruggeri sent Agüero onto the field as a substitute for Emanuel Rivas in the 69th minute of the match.

Following the arrival of coach Jose Omar Pastoriza, seven months after Agüero's first match he returned to the club's first-team in 4–2 win against Peru's Cienciano during the group stages of the 2004 Copa Libertadores.

[37] He ended his first season in Madrid with seven goals in all competitions, eased into European football by manager Javier Aguirre, who opted to bring him in and out of the line-up as Atlético finished seventh, enough to qualify for the UEFA Intertoto Cup.

Following the departure of strike partner Fernando Torres to Liverpool in the summer of 2007, Agüero secured his starting spot for the Rojiblancos and soon became arguably the team's most important player at the age of just 19.

In the 2007–08 season, he finished third highest scorer in La Liga, behind Dani Güiza and Luís Fabiano, with 19 goals, and was runner up in the Trofeo Alfredo Di Stéfano award.

[39][40] He also scored important goals against the likes of Real Madrid, Valencia, Sevilla and Villarreal to help Atlético finish fourth and qualify for the UEFA Champions League for the first time in over ten years.

[43] With the help of more vital goals in a formidable end of the season run-in from his team, Agüero finished in the top ten contenders for the Pichichi Trophy, which was won by his teammate Forlán.

Atlético were knocked out of the competition, but went on to reach the final of the 2009–10 UEFA Europa League, where Agüero assisted both goals in a 2–1 extra time win against English club Fulham.

He was an unused substitute in the Dublin Super Cup match against Inter Milan and the 2011 FA Community Shield against Manchester United with manager Roberto Mancini believing Agüero was not yet fit.

[70] Agüero made his League Cup debut in the quarter final match against Arsenal at the Emirates Stadium, scoring the only goal of the game in the 83rd minute from an Adam Johnson through-ball.

After being shown the red card, Barton proceeded to kick Agüero's knee, then attempted to attack Vincent Kompany, only for him to be held back by Micah Richards.

In the 94th minute, Agüero, receiving the ball from Balotelli, drove into the penalty area and placed a powerful low shot into the corner of the goal, clinching the win and the first top flight English title for Manchester City since 1968.

[117] The Times reported that he was the main transfer target of Spanish giants Real Madrid,[118] but Agüero responded by saying, "I'm very happy at City and I feel appreciated and loved here which means a lot to me.

[135] In his third appearance since returning from the hamstring problem, Agüero suffered a recurrence of the injury and was withdrawn at half-time in a 2–1 Champions League loss at Camp Nou against Barcelona.

[146] Five days later, in his 100th Premier League match, he was wrongly booked for simulation by referee Mike Jones after being fouled by José Fonte in the penalty area, although City went on to defeat Southampton 3–0.

[167][168] He returned on 21 November, scoring in a 1–4 home loss to Liverpool; this was his 85th Premier League goal, making him the top-scoring South American of all time in the division, ahead of his compatriot and former strike partner Carlos Tevez.

[174] On 13 August 2016, Agüero scored Manchester City's first competitive goal under the management of Pep Guardiola in a 2–1 victory against Sunderland on the opening day of the 2016–17 Premier League season.

[188] He opened the scoring in the 2018 EFL Cup Final on 25 February, by chipping Arsenal's David Ospina in a 1vs1 situation, ultimately helping City secure a convincing 3–0 victory at Wembley Stadium.

[200] On 10 February, Agüero scored his 11th Premier League hat-trick, as City defeated rivals Chelsea 6–0 at home;[201] with this feat, he equalled Shearer's record of 11 in the competition.

[204][205] On 10 August 2019, Agüero came on as a substitute replacing Gabriel Jesus, in a match that was dominated by the newly introduced VAR, at the London Stadium against West Ham United.

On 31 May 2021, Agüero agreed to sign for La Liga club Barcelona on a two-year contract starting 1 July, with a buyout clause set at €100 million.

At the 2007 FIFA U-20 World Cup, held in Canada, Agüero scored twice and helped set up three goals in a 6–0 win over Panama in the second game of the group stage of the tournament.

[231] Agüero was named in the Argentine squad for the 2015 Copa América, and in a warm-up game on 7 June against Bolivia in San Juan, he scored his first international hat-trick in a 5–0 victory.

[236] Agüero was included in Gerardo Martino's 23-man squad for the Copa América Centenario and scored his first goal of the tournament in Argentina's second group match, a 5–0 win over Panama on 10 June 2016, which allowed them to advance to the quarter-finals of the competition.

[244] In Argentina's final group match against Qatar on 23 June, Agüero scored the second goal in a 2–0 win, which enabled his team to advance to the knock-out stages.

[247] On 28 June 2021, Agüero made his 100th senior international appearance for Argentina in a 4–1 win against Bolivia in his team's final group stage match of the 2021 Copa América, also setting up Messi's second goal.

During the 2022 FIFA World Cup, Agüero was present with the winning Argentine team for the duration of the tournament as an unofficial supporter, as his heart conditions had forced his retirement a year earlier.

[256] Aguero has a diminutive figure with a stocky build, which has led to comparisons with former Manchester City teammate Carlos Tevez[257] and past forwards such as Romário,[250] Alessandro Del Piero,[255] and Diego Maradona.

[261] His ex-manager at Manchester City, Roberto Mancini, has compared Agüero to former Brazilian striker, Romário, due to his pace, goalscoring ability, positioning in the area, and technique.

[273] In November 2022, Agüero joined the newly established Kings League serving as chairman for one of the competing teams, Kunisports,[274] featuring as a guest player for his own side.