In the 1998–99 season, Barzagli made his first professional football appearance with semi-professional Rondinella[9] before moving to Serie B side Pistoiese in 2000–01,[9] in a co-ownership deal.

[18] He later credited his Wolfsburg coach during the 2008–09 season, Felix Magath, for having helped him to improve as a footballer and for instilling a stronger mentality and work ethic in him.

On 26 January 2011, Barzagli left Wolfsburg to return to Italy, joining Serie A giants Juventus for a contract of €300,000 fixed and €300,000 variable, which would keep him at the club until 2013.

[24] His first six months with the Bianconeri coincided with the second half of a terribly disappointing 2010–11 campaign under Luigi Delneri, which saw the club finish only seventh in Serie A, with Barzagli making 15 appearances in the league that season.

Most of these were made alongside Leonardo Bonucci and Giorgio Chiellini in Antonio Conte's now typical three-man backline and 3–5–2 formation, as the club again prevailed in Serie A, winning their second consecutive title, and made their way to the quarter-finals of the Champions League and the semi-finals of the Coppa Italia; due to their performances together, the three-man defence earned the nickname BBC, a reference to the players' initials,[30] and soon the trio established themselves as one of the best defences in world football during the following seasons.

[41] On 2 May 2015, Barzagli helped Juventus keep a clean sheet in a 1–0 away victory over Sampdoria, which allowed the Turin club to clinch the Serie A title for a fourth consecutive season.

[43] On 6 June, Barzagli started for Juventus in the 2015 UEFA Champions League final, ahead of his injured defensive teammate Chiellini, but were defeated 3–1 by Barcelona at Berlin's Olympiastadion.

[46][47] During the beginning of the 2015–16 season, Barzagli demonstrated his versatility by filling in for the recovering Stephan Lichtsteiner as a rightback; in this position, he made a series of impressive performances, including an assist for Álvaro Morata's opening goal in a 2–0 home win over Sevilla in the Champions League group stage on 30 September,[48] which earned him the Juventus Player of the Month Award for October.

[61] After initially struggling with injuries early on in the season, he returned to the starting line-up for the club's league fixture on 26 September, and made his 200th Serie A appearance with Juventus during the match, captaining the team in a 2–0 home win over Bologna.

[62][63] On 23 October, he made his 50th UEFA Champions League appearance (excluding qualifying rounds), coming on as a late substitute for Juan Cuadrado in a 1–0 away win over Manchester United.

[67] Barzagli was a member of the Italian under-21 side that conquered the 2004 UEFA European Under-21 Championship under the guidance of manager Claudio Gentile, and he also appeared at the Summer Olympics in Athens that year, winning a bronze medal.

[69] He was called up for the 2006 FIFA World Cup and,[70] while not expecting to play at all, was deployed as a substitute in a 1–0 victory against Australia in the second round, following Marco Materazzi's sending-off.

[76] He was selected to Italy's UEFA Euro 2008 squad,[77] and partnered alongside Materazzi in the heavy 0–3 defeat against the Netherlands,[78] after Italian skipper Fabio Cannavaro on 2 June suffered an injury in training.

[79] Barzagli later suffered an injury in training on 19 June, which kept him out for the rest of the tournament,[80] as Italy were eliminated on penalties in the quarter-finals by the eventual champions Spain.

[87] On 1 June 2012, in a preparation match for Euro 2012 against Russia, he captained the team for the first time after Gianluigi Buffon was taken off to be replaced by Morgan De Sanctis.

[91] On 18 June 2012, after recovering from his injury, Barzagli was picked over Leonardo Bonucci to play against Ireland alongside Juventus teammate Chiellini in Italy's last match of the Euro 2012 group stage.

[108] Following the defeat in what was initially thought to be the final international match of his career, a visibly emotional Barzagli stated in a press conference with RAI Sport: "We really did give everything.

[110] After speaking to Ventura, Barzagli stated in an interview in early August that he would consider continuing to play for the Italy national team if he were to receive a call-up;[111] on 27 August, he was officially called up to the national team once again for a friendly match against France on 1 September, and for Italy's first 2018 World Cup qualification match on 5 September, against Israel.

[114] Immediately following the second leg on 13 November, a 0–0 home draw which ultimately proved to be his 73rd and final international appearance, Barzagli announced his retirement from the national team.

[115] Following his retirement from professional football, Barzagli was appointed as a member of Juventus's defensive coaching staff under the club's new manager Maurizio Sarri in 2019.

[117] On 2 August 2021 it was confirmed, that Barzagli had been hired by the Italian Football Federation where he would have a general role helping the coaches at the various men’s national youth teams up to age Under-20.

"[83][125][126] Throughout his career with Italy and Juventus, the defensive trio of Barzagli, Bonucci, and Chiellini, which was dubbed the BBC in the media, was considered to be one of the greatest in history,[127] with pundits likening it to Italy's and Juventus's successful defensive trio of the 1930s, made up of full-backs Virginio Rosetta and Umberto Caligaris, as well as centre-half Luis Monti, who also won five consecutive league titles.

[128] Considered a "late-bloomer",[129] he stood out in Italy and in Europe during the 2010s, due to his marking, intelligence, aerial prowess, and precise tackling ability, as well as his correct behaviour, capacity to read the game, and his adeptness in one on one situations; these attributes enabled him to establish himself as one of the best defenders in Italy, and be voted to the Serie A Team of the Year for three consecutive seasons, also making him an important member of both his club and national sides.

[8][119][130][131] His calm composure, tactical awareness, consistency, technique, vision, and ball playing ability enabled him to be regarded as one of the best and most complete defenders in the world.