Having had an unsuccessful trial with Barcelona at age 15, Balotelli was signed by Inter Milan in 2006 on loan with a pre-set price of €150,000 to co-own the player.
In June 2007, Inter exercised the option and purchased the other half for an additional €190,000.
On 8 November 2007, as part of Sheffield F.C.'s 150th anniversary celebrations, Balotelli featured in a friendly between the two sides at Sheffield United's Bramall Lane.
The game finished 5–2 to Inter, with Balotelli scoring twice.
He made his first team and Serie A debut on 16 December 2007, replacing David Suazo in a 2–0 win against Cagliari.
Three days later, he was featured in the starting lineup in a Coppa Italia match against Reggina, scoring two goals in a 4–1 win.
Balotelli gained national attention after he scored two goals against Juventus in the return leg of the Coppa Italia quarter-finals, being instrumental in a 3–2 away win for Inter.
His first Serie A goal then came in April 2008 in a 2–0 away win against Atalanta.
Inter went on to win the 2007–08 Serie A. Balotelli was a substitute in the 2008 Supercoppa Italiana final against Roma; he came on as a replacement for Luís Figo, scoring in the 83rd minute.
Inter went on to win the final 6–5 on penalties after the match ended 2–2.

In November 2008, Balotelli became the youngest Inter player (at 18 years and 85 days) to score in the UEFA Champions League when he scored a goal in a 3–3 draw against Cypriot side Anorthosis Famagusta, beating the previous record set by Obafemi Martins (at 18 years and 145 days).
In an April 2009 match with Juventus where he scored Inter's only goal in a 1–1 draw, Balotelli was racially abused by Juventus fans throughout the match.
This led Inter owner Massimo Moratti to say he would have pulled the team off the pitch had he been present.
The racist chants were also condemned by Juventus chairman Giovanni Cobolli Gigli, and Juventus were issued a one-match home-fan ban because of the incident.
Inter won Serie A for the fourth time in a row.

In his second season with Inter, Balotelli had several disciplinary problems, most notably involving head coach José Mourinho, who excluded him from the first team in the second half of January 2009.
Earlier that season, Mourinho had accused Balotelli of showing a lack of effort in training, saying, "[A]s far as I'm concerned, a young boy like him cannot allow himself to train less than people like Figo, Córdoba, and Zanetti."
Balotelli continued to be the subject of racist chants throughout the season, becoming the focus of Juventus fans even during matches not involving Inter, leading to Juventus being fined twice and the club ultimately punished with a partial stadium closure.

Balotelli's disciplinary problems and his difficult relationship with Mourinho continued in the 2009–10 season.
In November 2009, Inter drew 1–1 against Roma, after which Mourinho criticized his players, going as far as saying Balotelli "came close to a zero rating".
Balotelli had another negative encounter with Juventus fans in the heated Derby d'Italia encounter in an away match against Juventus on 5 December 2009, which Inter lost 2–1.
When he was elbowed by Juventus midfielder Felipe Melo in the shoulder, Balotelli fell theatrically onto the pitch, for which he was booked, while Melo was sent off for a second yellow card.
The incident sparked an altercation between Balotelli's teammate Thiago Motta and Juventus goalkeeper Gianluigi Buffon.
The tension between Balotelli and Mourinho reached its peak on the eve of the UEFA Champions League second leg against Chelsea after the young striker was not called-up, following an altercation with his manager.
Despite Inter's 1–0 win at Stamford Bridge, Balotelli was criticized by several senior players, including captain Javier Zanetti and veteran defender Marco Materazzi, as well as by his own agent.
In March 2010, he came under heavy criticism from fans after he publicly sported a Milan shirt on the Italian show Striscia la Notizia.

Balotelli released a statement of apology in Inter's official website that read:
I
Having had an unsuccessful trial with Barcelona at age 15, Balotelli was signed by Inter Milan in 2006 on loan with a pre-set price of €150,000 to co-own the player. In June 2007, Inter exercised the option and purchased the other half for an additional €190,000. On 8 November 2007, as part of Sheffield F.C.'s 150th anniversary celebrations, Balotelli featured in a friendly between the two sides at Sheffield United's Bramall Lane. The game finished 5–2 to Inter, with Balotelli scoring twice. He made his first team and Serie A debut on 16 December 2007, replacing David Suazo in a 2–0 win against Cagliari. Three days later, he was featured in the starting lineup in a Coppa Italia match against Reggina, scoring two goals in a 4–1 win. Balotelli gained national attention after he scored two goals against Juventus in the return leg of the Coppa Italia quarter-finals, being instrumental in a 3–2 away win for Inter. His first Serie A goal then came in April 2008 in a 2–0 away win against Atalanta. Inter went on to win the 2007–08 Serie A. Balotelli was a substitute in the 2008 Supercoppa Italiana final against Roma; he came on as a replacement for Luís Figo, scoring in the 83rd minute. Inter went on to win the final 6–5 on penalties after the match ended 2–2.
In November 2008, Balotelli became the youngest Inter player (at 18 years and 85 days) to score in the UEFA Champions League when he scored a goal in a 3–3 draw against Cypriot side Anorthosis Famagusta, beating the previous record set by Obafemi Martins (at 18 years and 145 days). In an April 2009 match with Juventus where he scored Inter's only goal in a 1–1 draw, Balotelli was racially abused by Juventus fans throughout the match. This led Inter owner Massimo Moratti to say he would have pulled the team off the pitch had he been present. The racist chants were also condemned by Juventus chairman Giovanni Cobolli Gigli, and Juventus were issued a one-match home-fan ban because of the incident. Inter won Serie A for the fourth time in a row.
In his second season with Inter, Balotelli had several disciplinary problems, most notably involving head coach José Mourinho, who excluded him from the first team in the second half of January 2009. Earlier that season, Mourinho had accused Balotelli of showing a lack of effort in training, saying, "[A]s far as I'm concerned, a young boy like him cannot allow himself to train less than people like Figo, Córdoba, and Zanetti." Balotelli continued to be the subject of racist chants throughout the season, becoming the focus of Juventus fans even during matches not involving Inter, leading to Juventus being fined twice and the club ultimately punished with a partial stadium closure.
Balotelli's disciplinary problems and his difficult relationship with Mourinho continued in the 2009–10 season. In November 2009, Inter drew 1–1 against Roma, after which Mourinho criticized his players, going as far as saying Balotelli "came close to a zero rating". Balotelli had another negative encounter with Juventus fans in the heated Derby d'Italia encounter in an away match against Juventus on 5 December 2009, which Inter lost 2–1. When he was elbowed by Juventus midfielder Felipe Melo in the shoulder, Balotelli fell theatrically onto the pitch, for which he was booked, while Melo was sent off for a second yellow card. The incident sparked an altercation between Balotelli's teammate Thiago Motta and Juventus goalkeeper Gianluigi Buffon. The tension between Balotelli and Mourinho reached its peak on the eve of the UEFA Champions League second leg against Chelsea after the young striker was not called-up, following an altercation with his manager. Despite Inter's 1–0 win at Stamford Bridge, Balotelli was criticized by several senior players, including captain Javier Zanetti and veteran defender Marco Materazzi, as well as by his own agent. In March 2010, he came under heavy criticism from fans after he publicly sported a Milan shirt on the Italian show Striscia la Notizia.
Balotelli released a statement of apology in Inter's official website that read:
I
Mario Balotelli