Squillaci began his football career playing for hometown club FC Seynois in the commune of La Seyne-sur-Mer. In 1996, he joined Sporting Toulon and made his professional debut in the 1997–98 season, while the club was playing in Ligue 2. After a year with Toulon, Squillaci joined Monaco. He spent two seasons on the club's reserve team before joining AC Ajaccio on loan for two years. Squillaci returned to Monaco in 2002 and contributed to the team that won the Coupe de la Ligue in 2003. He also featured in European competition for the first time in his career and, in the 2003–04 season, played on the Monaco team that reached the 2004 UEFA Champions League Final. In the same season, Squillaci was named to the National Union of Professional Footballers (UNFP) Ligue 1 Team of the Year. In 2006, Squillaci signed a long-term contract with league rivals Olympique Lyonnais and won two consecutive league titles, as well as the Coupe de France in 2008 before departing for Spain in 2008 to join Sevilla. With Sevilla, he appeared in over 65 matches and won the Copa del Rey in his final season with the club. In 2010, Squillaci signed a three-year contract with English club Arsenal where he also reached 2011's Football League Cup final.
Squillaci is a former France international. Prior to playing at senior level, he played at under-20 and under-21 level. At under-21 level, he played on the team that won the bronze medal at the 2001 Mediterranean Games. Squillaci made his senior international debut in August 2004 in a friendly match against Bosnia and Herzegovina. He has participated in UEFA Euro 2008, as well as the 2010 FIFA World Cup for his nation.
Squillaci was born in the commune of Toulon and was raised in nearby La Seyne-sur-Mer. On 12 May 2007, for his positive representation of La Seyne, the commune honoured the player by naming a stadium after him. The Stade de Squillaci is currently being occupied by amateur club Avenir Sportif de Mar. Squillaci is of Corsican descent through both his mother and father. The couple moved to the mainland from the commune of Ghisonaccia in Haute-Corse. Squillaci is married and has a son, Aaron. He is a member of Champions for Peace, which is a group of 54 athletes that are committed to serving peace in the world through sport. The group was created by Peace and Sport, a Monaco-based international organisation.
Squillaci began his football career playing for hometown club FC Seynois. While training at La Seyne, he was described by his coach Franck Seva as a "lovely, quiet boy". Squillaci spent a decade at the club before moving to professional club Sporting Toulon in 1996 at age 16. He was originally a defensive midfielder and spent only one season in the club's youth academy, where he was supervised by former club player Christian Dalger. Squillaci began the 1997–98 season playing on the club's reserve team. Following the firing of Albert Emon mid-season, he was replaced with Dalger. In March 1998, Dalger, subsequently, called up Squillaci to the first team and he made his professional debut on 7 March 1998 in a 1–0 league win over Nice appearing as a substitute for Victor Agali. With Toulon in a relegation battle, Squillaci made substitute appearances in wins over Lille, Le Mans, and Lorient and defeats to Martigues and Red Star Paris. Toulon ultimately finished the campaign in 20th place, which resulted in the club's relegation to the Championnat National, the third level of French football. Squillaci finished the season with five appearances in the league and one in the Coupe de France. Toulon, surprisingly, reached the Round of 16 in the latter competition.
Due to not being under a professional contract while playing with Toulon, Squillaci was allowed to leave the club on a free transfer. He was recruited by Monaco and joined the club in 1998. Following his signing, Squillaci was inserted onto the club's reserve team, which was playing in the Championnat de France amateur, the fourth level of French football. He spent two years playing on the club's reserve team from 1998 to 2000 amassing over 45 appearances. After failing to establish himself under Claude Puel, Monaco officials announced that Squillaci would be heading to Corsica to join Ligue 2 club AC Ajaccio on loan. In two seasons with the club, Squillaci appeared in over 70 matches and helped the club achieve promotion to Ligue 2.