[2] He played for the Primavera team from 2011 to 2014,[3] (2013–14 season as an overage player), and on 5 May 2014, Caldara made his professional debut coming on as a second-half substitute in a Serie A match against Catania.

[11] After impressing newly appointed head coach Gian Piero Gasperini during pre-season, Caldara cemented a first-team place for the 2016–17 season; in manager's favored 3–4–3 formation, he began to play in the center of a back three.

[26] Following the end of his loan deal with Atalanta, Caldara moved to Turin, where on 13 July 2018 he was officially presented as Juventus player and given the number 13 jersey with his last name on.

[27] He played his debut and only game for Juventus on 25 July 2018, an International Champions Cup friendly against Bayern Munich, replacing captain Giorgio Chiellini eight minutes into the second half.

[28] On 2 August 2018, Caldara was signed by AC Milan on a five-year contract for €35 million payable in two years, with Leonardo Bonucci moving in the opposite direction in a similar deal.

[32] On 20 September 2018, Caldara made his official debut for Milan, playing as a starter alongside Romagnoli in a Europa League away match against F91 Dudelange.

[35] In April, a few days after Milan's 1–0 Coppa Italia semifinal loss to Lazio at the San Siro, in which Caldara played for 65 minutes as a starter, he suffered an even worse training injury, rupturing his left anterior cruciate ligament, which sidelined him for another period of 6 months.

[38][39] Having recovered from his ACL injury, he resumed training sessions at full capacity on 9 October 2019, which coincided with Stefano Pioli's first day in Milan as a head coach.

[40] However, as Pioli was still reluctant to include Caldara in the first team line-ups 3 months since his full recovery from injuries, he submitted a loan or transfer request in early January 2020.

[45] On 19 February 2020, Caldara made his UEFA Champions League debut, playing for 75 minutes as a starter in a 4–1 home win against Valencia at the San Siro.

[51][52] Generally considered out of the club's senior team project by head coach Stefano Pioli and the board of directors, he was put on the transfer market immediately after his return.

[55][56] In September, he also became a surprise inclusion on the team's squad list for the Champions League, mainly due to regulations that allow each club to register four homegrown players.

[57] However, just days before start of the competition, Caldara had a surgery on his right ankle, the recovery from which ruled him out for at least three months, which effectively made him miss all the group matches.

[60] On 25 May 2024, after almost six years since his transfer to AC Milan, Caldara played his first and the only game for the club in Serie A, coming on as a substitute for Matteo Gabbia in the second half of the eventual 3-3 draw against Salernitana at San Siro on the final matchday of the season.