He moved to Europe to spend the 1998–99 and 1999–2000 seasons with Italian team Basket Viola Reggio Calabria. In 1999, he teamed with Brent Scott, Brian Oliver and Sydney Johnson to earn promotion from the Italian 2nd Division to the Italian 1st Division.

Ginóbili comes from a family of basketball players. His oldest brother, Leandro, retired in 2003 after seven years in the Argentine basketball league, while brother Sebastián has played in both the Argentine local league and in the Spanish 2nd-tier level Liga Española de Baloncesto. Their father Jorge was a coach at a club in Bahía Blanca, Argentina, where Ginóbili learned to play the game. Given the proliferation of basketball clubs in Bahía Blanca and his idolization of Michael Jordan, Ginóbili’s love for basketball grew rapidly.

In the 2003–04 season, the Spurs began featuring Ginóbili more prominently, starting him in half of the 77 regular season games in which he played. His statistics improved in all major categories, as he averaged 12.8 points, 4.5 rebounds, 3.8 assists and 1.8 steals per game. During the 2004 playoffs, the Spurs lost again to the Los Angeles Lakers in the Western Conference Semifinals. Following Game 5 where Derek Fisher scored a buzzer-beating jump shot, the Spurs lost Game 6 and the series 4–2. While Ginóbili did not start in a single playoff game as he did in 2003, his playoff statistics improved significantly, with 13.0 points, 5.3 rebounds and 3.1 assists per game.

Ginóbili has dual citizenship with Argentina and Italy, thanks to his Marchesan descent. As a result of his travels, he can speak Spanish, Italian and English fluently. In his free time, Ginóbili enjoys listening to Latin music, watching movies and traveling. In 2004, he married fellow Argentine Marianela Oroño. On 16 May 2010, his wife gave birth to twin boys, Dante and Nicola. On 21 April 2014, his wife gave birth to their third son, Luca.

Ginobili was known as a team player. He accepted the Spurs coaches’ decision to bring him off the bench for most of his career. He was also known for his difficult-to-defend passes, including the no-look pass. Ginobili was also willing to draw charges on defense. In 2007, he was listed by ESPN writer Thomas Neumann at No. 6 on the list of greatest floppers in NBA history. Five years later, Ian Thomsen, a Sports Illustrated columnist, grouped Ginóbili with fellow European league players Anderson Varejão and Vlade Divac as the players who “made [flopping] famous”, by exaggerating contact on the court in a manner analogous to diving in soccer games.

In 2007, ESPN sportswriter John Hollinger ranked Ginóbili as the sixth-best international player then active in the NBA, describing Ginobili as “one of the great draft heists of all time” and attributing the trend of NBA teams drafting developing European players to the success of the Argentine. The following year, Ginóbili was named by ESPN as one of the best EuroLeague players to have graced the NBA.

Ginóbili was to play an even bigger role for the Spurs the following season, reaching career high averages in points, rebounds, assists, and three-point field goal percentage. On 11 February 2008, Ginóbili scored 34 points and recorded 15 rebounds in a 93–88 win over the Toronto Raptors, becoming the first guard in Spurs’ history to have at least 15 points and 15 rebounds in a game. On 21 April 2008, the NBA announced that Ginóbili had won the 2008 Sixth Man Award, winning 123 out of the 124 first place votes. (self.nba) Ginobili had a statline of 19.5 points, 4.5 assists, and 4.8 rebounds on .460 shooting averaging 31.1 minutes. Only a couple of weeks later, the Argentine was also named to the All-NBA Third Team. In the playoffs, the Spurs defeated the Suns 4–1 in the first round, Ginóbili was moved to the starting lineup in the second round against the New Orleans Hornets after the Spurs lost the first two road games. San Antonio eventually prevailed in seven games, the Argentine played another strong series, leading the Spurs in points and assists per game (21.3 and 6.0 respectively). However, San Antonio lost to arch-rivals Los Angeles Lakers in the Conference Finals in five games, and once again failed to capture back-to-back NBA championships.

On 31 October 2009, in a game against the Sacramento Kings, a bat descended onto the court at the AT&T Center, causing a stoppage of play. As the bat flew past, Ginóbili swatted the bat to the ground with his hand. He then carried the creature off the court, earning the applause of the crowd. On 9 April 2010, the Spurs and Ginóbili agreed to a three-year, $39 million contract extension through the 2012–13 season.

He played with Argentina at the 2006 FIBA World Championship, where his team finished in 4th place. Ginóbili was the flag bearer for Argentina at the opening ceremony of the 2008 Summer Olympics, which was held in Beijing, China. At the 2008 Beijing Summer Olympics basketball tournament, Ginóbili’s Argentina defeated Lithuania to win the bronze medal game, although the shooting guard did not play in that match, after sustaining an injury in the tournament’s semifinals. In April 2010, Ginóbili announced that he would not participate in the 2010 FIBA World Championship, due to family reasons. He did however compete for the team at the 2012 London Summer Olympics, where Argentina narrowly missed out on winning the bronze medal, in the bronze medal game versus Russia. He played his last international games at the 2016 Rio Summer Olympics, where Argentina finished in 8th place.

On 11 July 2013, Ginóbili re-signed with the Spurs on a two-year deal. In 2013–14, the Spurs had a league-best 62–20 record. Ginóbili finished third in the voting for Sixth Man of the Year. In game 1 of the Western Conference Finals against the Thunder, Duncan-Ginóbili-Parker won their 110th career game in the playoffs, matching Magic Johnson, Kareem Abdul-Jabbar and Michael Cooper from the Los Angeles Lakers. The Spurs reached the NBA Finals again, where they faced the Heat for the second year in a row. This time, they dominated the series, winning 4–1 to claim that franchise’s fifth championship; Ginóbili won his fourth championship as a Spur.

On 20 July 2015, Ginóbili re-signed with the Spurs. On 14 January 2016, in a win over the Cleveland Cavaliers, Ginóbili played his 900th NBA game, all with the Spurs. On 4 February, he underwent surgery after suffering a testicular injury in the Spurs’ win over the New Orleans Pelicans the previous night. He was subsequently sidelined for one month. He returned to the action on 5 March, after missing 12 games with the injury, scoring 22 points in 15 minutes against the Sacramento Kings.

On 14 July 2016, Ginóbili re-signed with the Spurs. On 9 November 2016, in a loss to the Houston Rockets, Ginóbili became the 15th second-rounder to reach 13,000 points and joined Rashard Lewis as the only second round draft picks in NBA history with 13,000 career points and at least 1,300 three-pointers.

On 24 August 2017, Ginóbili re-signed with the Spurs. In January 2018, he became the only player in NBA history to have multiple 20-point games off the bench at age 40 or older. He also became the first player in his 40s to score 15-plus points in back-to-back games since Michael Jordan in 2002–03. On 28 January against the Sacramento Kings, Ginóbili and Vince Carter scored 21 and 15 points respectively; it was the first game in NBA history where two players over the age of 40 scored more than 15 points. On 29 March 2018, in a 103–99 win over the Thunder, Ginobili became the Spurs’ career leader in steals, passing David Robinson (1,388) for the franchise record. In game 4 of the Spurs’ first round playoff series against the Warriors, Ginóbili played in his 217th playoff game, breaking a tie with Shaquille O’Neal for sixth in league history. Ginóbili also passed Reggie Miller for third in career 3-pointers in playoff history. The Spurs lost to the Warriors in five games.

On 27 August 2018, Ginóbili announced his retirement from professional basketball, making him the second player that season to complete a career with one team, after Nick Collison of the Oklahoma City Thunder. On 28 March 2019, the Spurs retired Ginóbili’s No. 20 jersey, right next to the No. 21 jersey of Tim Duncan.