De Sciglio made his professional debut for Milan in 2011, after several seasons in the club's youth system, and subsequently became a regular in the line-up, being able to play as either right or left back, winning two Supercoppa Italiana titles.

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,[3] before moving to local amateur team Cimiano in 2001.

[7] 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.

[7][10] The following month, on 6 May, he played in his first Milan derby against city rivals Inter,[11] replacing an injured Daniele Bonera midway through the first half of a 4–2 loss.

[12] As from the 2012–13 season De Sciglio was assigned the number 2 shirt, which he called "very important" as in the past it was worn "by great players like Mauro Tassotti and Cafu", adding that he hoped to "live up to their standards".

[15] De Sciglio made 18 appearances for Milan in the 2014–15 season as he struggled with injury and vied with Ignazio Abate for the starting right-back spot.

[30] De Sciglio won eight caps for Italy under-19 between 2010 and 2011,[31] including two appearances and one goal in the 2011 UEFA European Under-19 Football Championship qualifying round.

[31] 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.

[44][45] 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.

[7][47][49] Former Milan player Alberigo Evani, who coached him during the 2007–08 season,[5] described De Sciglio as "a fast runner, with good technique", and also as "a versatile footballer".

[50] Along with fellow Italian fullback Davide Santon, De Sciglio's precocious displays for Milan and the Italy national side led players, managers and pundits to describe him as the heir apparent of Paolo Maldini in 2013;[51] he has also been compared to former Milan right-back Mauro Tassotti,[52] who noted that De Sciglio reminded him of himself due to his athleticism and stamina.