A native of Milan, De Sciglio started playing football as a child at the Santa Chiara e San Francesco parish recreation centre in the nearby municipality of Rozzano, before moving to local amateur team Cimiano in 2001.

The following year, aged ten, he joined A.C. Milan’s youth system, where he spent nine seasons. In 2010, he was a member of the under-20 squad who won the Coppa Italia Primavera, 25 years after the team’s last success in the competition.

At the start of the 2011–12 season De Sciglio was officially included in the first team squad by manager Massimiliano Allegri. He made his professional debut on 28 September 2011, coming on as a substitute in a UEFA Champions League group stage home game against Viktoria Plzeň, which Milan won 2–0. He was given his first start (and second overall appearance) in a 2–2 away draw against the same team on 6 December. Four months later, on 10 April, De Sciglio also made his league debut, playing as a starter in a 1–0 away win over Chievo. The following month, on 6 May, he played in his first Milan derby against city rivals Inter, replacing an injured Daniele Bonera midway through the first half of a 4–2 loss.

De Sciglio won eight caps for Italy under-19 between 2010 and 2011, including two appearances and one goal in the 2011 UEFA European Under-19 Football Championship qualifying round. Subsequently, he represented Italy under-20, winning five caps between 2011 and 2012. On 25 April 2012, he made his debut for Italy under-21, coming on as a substitute midway through the second half of a friendly match against Scotland, which Italy won 4–1. For the under-21 side, he went on to make four further appearances, all in 2012.

Less than four months after making his debut for the under-21 side, De Sciglio received his first call-up to the Italy senior team, as manager Cesare Prandelli named him to the squad for a friendly match against England to be played on 15 August 2012. However, he was left as an unused substitute in the 2–1 defeat. He went on to make his debut for the senior team on 21 March 2013, in a friendly match against Brazil that ended in a 2–2 draw.

At the 2013 FIFA Confederations Cup De Sciglio played in four games out of five, including the third-place match against Uruguay that Italy won on penalties following a 2–2 draw after extra time, even though De Sciglio had missed his spot kick in the eventual 3–2 win.

De Sciglio is primarily a right-sided full-back or wing-back, who can also play comfortably on the left side due to his ability with his left foot as well as his stronger right foot; he has also been deployed as a wide midfielder on occasion, or even as a centre-back, a position which he formerly played in his youth. Former Milan player Alberigo Evani, who coached him during the 2007–08 season, described De Sciglio as “a fast runner, with good technique”, and also as “a versatile footballer”. Along with fellow Italian fullback Davide Santon, De Sciglio’s precocious displays for Milan and the Italian national side led players, managers and pundits to describe him as the heir apparent of Paolo Maldini in 2013; he has also been compared to former Milan right-back Mauro Tassotti, who noted that De Sciglio reminded him of himself due to his athleticism and stamina. His managers have also praised him for his maturity, tenacity and composure, both when attacking or defending. A solid, defensive-minded full-back, he is mainly known for his consistency, decision-making, positioning, and tactical intelligence, as well as his ability to read the game and time his challenges.

The 2013–14 season was a frustrating one for De Sciglio. He missed 20 matches in total due to various injuries which limited him to making just 21 appearances for the season in all competitions. On May 18, De Sciglio was sent off in Milan’s game against Sassuolo. De Sciglio healed in time to participate with his national side Italy in the 2014 World Cup in Brazil

After appearing in Italy’s 2014 FIFA World Cup qualifying campaign, De Sciglio was chosen under Prandelli to take part at the 2014 FIFA World Cup. He made his World Cup debut during the tournament, starting in Italy’s final group match against Uruguay, although Italy were eliminated in the first round following a 1–0 defeat.

Inzaghi’s replacement as coach, Siniša Mihajlović, has firmly established De Sciglio in the right-back position, having started him in almost every game this season, mostly replacing Abate on the right-back but also playing in place of the injured left-back Luca Antonelli. On 6 March 2016, De Sciglio made his 100th Milan appearance, being given the captain’s armband to mark the occasion, in a 2–0 away loss to Sassuolo.

Under the new Milan manager, Vincenzo Montella, De Sciglio started almost every match, mostly as a left-back. On 23 December 2016, he started the match against Juventus in the Supercoppa Italiana, which Milan went on to win 4–3 in a penalty shoot-out, with De Sciglio winning his second Supercoppa Italiana title.

On 31 May 2016, De Sciglio was named to Antonio Conte’s 23-man Italy squad for UEFA Euro 2016. After having been benched for Italy’s first two games, he was highly praised for his performances in Italy’s final group match against Republic of Ireland (a 1–0 loss) and Italy’s round of 16 match against Spain (a 2–0 victory).

On 3 July 2016, he started the quarterfinal match against Germany; following a 1–1 draw after extra-time, he successfully converted his penalty in the resulting shoot-out, but Italy were eventually eliminated from the tournament by a 6–5 defeat.

On 20 July 2017, De Sciglio joined Juventus for €12 million on a five-year contract. On 13 August, he made his club debut, coming on as a substitute in a 3–2 defeat to Lazio in the 2017 Supercoppa Italiana. On 26 November, De Sciglio scored his first ever goal, in a 3–0 home win over Crotone. After struggling in his later seasons at Milan to replicate the promising performances he had shown in his early years at the club, De Sciglio’s form improved significantly after his move to Juventus, and his consistent defensive performances drew praise in the media.

De Sciglio missed the first part of the 2018–19 season after picking up an injury during the pre-season. He returned to action on 27 October 2018, in a 2–1 away win over Empoli in Serie A.

On 5 October 2020, De Sciglio was signed by Lyon on a season-long loan.