Azpilicueta earned 55 caps for Spain at youth level in all age groups, and represented the under-21s in two European Championships, winning the 2011 edition.

A product of hometown club CA Osasuna's youth system, he made his La Liga debut on 8 April 2007 in a 0–2 away loss against Real Madrid, while still registered with the reserve team;[8] he started his career as a forward then switched to midfielder[9] and, throughout both his club and international career (senior and youth), appeared in several positions, including centre-back and central midfielder.

On 21 June 2010, French club Olympique de Marseille confirmed an agreement had been reached with Osasuna for the transfer of Azpilicueta, in a four-year contract for €7 million.

[14] On 27 November 2010, in the early minutes of a 4–0 home win against Montpellier – which meant Marseille climbed to the top of the league – Azpilicueta ruptured the anterior cruciate ligament in his left knee.

"[21] Due to his surname being difficult for some speakers of English to pronounce, club fans gave him the mononymous nickname "Dave".

[23] He played his first Premier League game the following week, coming on as a substitute for Branislav Ivanović in a 4–1 success over Norwich City, also at Stamford Bridge.

[25] He played 48 official contests in his first year with the Rafael Benítez-led side, including eight in the Blues' victorious campaign in the UEFA Europa League.

[26] Azpilicueta scored his first competitive goal for Chelsea on 29 October 2013, netting the first in a 2–0 victory at Arsenal in the fourth round of the League Cup.

[27] Following the arrival of new manager José Mourinho, he began appearing regularly as a left-back, taking the place of longtime incumbent Ashley Cole.

[32] On 2 September 2014, he signed a new five-year contract with the club[33] and on 18 October, he was sent off in the first half of a 2–1 win at Crystal Palace for a foul on Mile Jedinak.

[38] Although Azpilicueta was initially used as a left-back under new coach Antonio Conte, after two consecutive league defeats the latter converted into a back-three formation, with the former playing as a centre-back in the following match against Hull City on 1 October 2016, which ended in a 2–0 away win.

[47] After Cahill left Chelsea, he was named club captain ahead of the 2019–20 season; he had already worn the armband on the pitch while the Englishman was out of the team, including in the Europa League final victory against Arsenal in Azerbaijan.

[49][50] On 1 January 2020, Azpilicueta marked his 100th appearance as club captain with a goal and being named man of the match in the 1–1 draw against Brighton & Hove Albion.

[53] On 23 May, the final matchday of the league season, he was sent off for appearing to strike Aston Villa's Jack Grealish during a 1–2 defeat, but the three-game suspension was overturned on appeal.

[66][67] His departure was confirmed via a video message he shared on social media, wherein he signed off as "Your captain Cesar Azpilicueta, aka 'Dave' ".

[68] Following the departure from Chelsea, Azpilicueta returned to La Liga after 13 years and joined Atlético Madrid by signing a one-year contract.

On 11 May 2010, 20-year-old Azpilicueta was named by senior side manager Vicente del Bosque in a provisional list of 30 players, in view of the forthcoming edition of the FIFA World Cup.

[81] Azpilicueta was selected to the 2013 FIFA Confederations Cup tournament held in Brazil:[82] he started in the second group game against Tahiti which Spain won 10–0 in a record for the largest margin of victory in the competition,[83] and replaced Álvaro Arbeloa at half-time in the final against the hosts, in an eventual 3–0 loss.

[103] Since 2018, Azpilicueta has been a board member and co-owner of English non-league side Hashtag United, which plays in the Isthmian League Premier Division.

[106] He is part-owner along with Jose Antonio Cacho and Jesus Rincon, both of whom are top players in Spain with millions of YouTube subscribers.