The son of Carlos and Cristina Delfino, he began his professional career playing in the Argentine Basketball League for Olimpia de Venado Tuerto in the 1998–99 season, and he then transferred to Unión de Santa Fe in 1999–2000.
Delfino moved to Italy in 2000 and played four seasons in the Italian A League, the first two with Reggio Calabria and the other two seasons with Skipper Bologna.
In his first season in Italy, he played for Reggio Calabria. In just under 21 minutes per game he averaged 8.8 points, 2.5 rebounds and 1.9 steals. He scored a season-high 25 points in his second game against Scavolini Pesaro, making five of eight three-point attempts. He scored 15 points in just 20 minutes against Cordivari Roseto and tallied 14 points apiece against Paf Bologna, Muller Verona and Kinder Bologna. He hit at least one three-pointer in 19 of 24 games.
In his first season with Skipper Bologna, he moved into the starting lineup in the third game of the season and averaged about 26 minutes. He scored 18 points, including shooting 3-of-5 from three-point range, versus Euro Roseto and posted double-doubles against Benetton Treviso (13 points, 13 rebounds), Oregon Scientific Cantù (15 points, 11 rebounds) and Pippo Milano (14 points, 11 rebounds). He suffered torn ligaments in his ankle late in the season, but returned in late May.
Beginning in 2004, Delfino signed to play for the Detroit Pistons of the National Basketball Association, who made him the 25th pick in the first round of the 2003 NBA Draft, making him the first Argentine player ever to be selected in the first round of the NBA Draft. In November 2004, he suffered a knee injury that kept him on the injured list for over three months. He had an operation in the U.S. and then another in Argentina, where he recovered. However, Delfino did not immediately return to form after his rehabilitation, and was left off the Pistons' 2005 playoff roster. After he recovered from the knee injury, Delfino averaged 15.3 minutes, 3.9 points, 1.8 rebounds, and 1.3 assists per game in 30 games under coach Larry Brown. Many regarded Brown as having limited space for Delfino's offensive creativity. It was perceived that under the Pistons upcoming new coach Flip Saunders, that Delfino would thrive.
In his second season on the Pistons' active roster, Carlos averaged 10.7 minutes, 3.6 points, 1.7 rebounds, and 0.6 assists per game. Delfino played off the bench substituting for either Tayshaun Prince or Richard Hamilton. He had three straight games where he scored in double digits before being sidelined for the next 4 with the flu. Delfino became an important change-of-pace player in Flip Saunders' offensive scheme.
On June 15, 2007, the Detroit Pistons traded Delfino to the Toronto Raptors for 2nd round draft picks in both the 2009 NBA Draft and the 2011 NBA Draft. The 2007–08 season was his most productive in the NBA, as he averaged 9 points, 4.4 rebounds and 1.8 assists per game during the regular season.
On June 16, 2009, the Toronto Raptors extended a qualifying offer to Delfino.
In the summer of 2008, Delfino signed a 3-year contract with the Russian Super League club Khimki Moscow Region. Delfino was one of the highest paid basketball players in Europe, earning about $10 million US dollars per season, plus a house, a car and a driver, and savings on taxes. He averaged 13.0 points, 3.6 rebounds, 2.6 assists, and 1.5 steals per game in Europe's secondary level competition, the EuroCup, during the 2008–09 season.
On August 18, 2009, the Raptors signed and traded Delfino to the Milwaukee Bucks along with Roko Ukić in exchange for Amir Johnson and Sonny Weems.
Delfino had a breakout season with the Bucks, as he posted career highs in points per game, rebounds per game, assists per game, steals per game and blocks per game, while playing 30 minutes per game. He also played a major role in the playoffs, shooting a career high .405 from behind the 3-point line.
On August 20, 2012, Delfino signed with the Houston Rockets. After being a starter for three years in Milwaukee, Delfino became the sixth man for the Rockets in 2012–13. On June 30, 2013, Delfino was waived by the Rockets.
On July 17, 2013, Delfino signed with the Milwaukee Bucks. However, he never appeared in a game for the Bucks during the 2013–14 season due to a broken foot.
On August 26, 2014, Delfino was traded, along with Miroslav Raduljica and a 2015 second round draft pick, to the Los Angeles Clippers in exchange for Jared Dudley and a 2017 conditional first round draft pick. Three days later, he was waived by the Clippers.
On March 6, 2017, Delfino signed with the Argentine team Boca Juniors.
Delfino was a member of Argentina's junior national team that won the bronze medal at the 2001 FIBA Under-21 World Championship that was held in Saitama, Japan. Delfino was also a part of the senior Argentine national basketball team that won the gold at the 2004 Summer Olympic Games. He also played with Argentina's senior national team at the 2006 FIBA World Championship and at the 2008 Summer Olympic Games, where he helped Argentina to win the bronze medal. After years of absence following injury, he played with Argentina's senior basketball team at the 2016 Summer Olympic Games.
Note: The EuroLeague is not the only competition in which the player participated for the team during the season. He also played in domestic competition, and regional competition if applicable.