Born in Montevideo, Cáceres started his career with his local team Defensor, becoming a regular at a young age and competing in one full Primera División season with them.

[6][7] Upon arriving at Villarreal, Cáceres was immediately sent on loan to fellow La Liga side Recreativo de Huelva,[8] being one of the most used players during the season and often partnering Beto in central defence as the Andalusians managed to retain their division status, finishing in 16th position; on 9 January 2008, he scored against the club that owned his rights in the Copa del Rey (1–0 home win, but 2–1 loss on aggregate),[9] and never appeared officially for them.

[12] He appeared in three games in the campaign's UEFA Champions League – two starts, 217 minutes – being an unused substitute in the final against Manchester United which completed the treble for the Catalans.

[16] He began as a regular under Ciro Ferrara, but his campaign would be ultimately disrupted by a number of injuries, including one in January 2010 that put him out of action for several months.

The Dane was given a straight red card, and the South American was initially ruled out for the rest of the campaign,[20] but unexpectedly recovered for the final two games,[21] with his side finishing fifth and qualifying for the UEFA Europa League.

[24] He made his debut for Juve in his second spell on 8 February 2012, playing the full 90 minutes in a 2–1 away win against AC Milan in the semi-finals of the Coppa Italia and scoring both of his team's goals.

[30][31] In late September, however, he had his driving license revoked for six months and was suspended by the club after crashing his Ferrari into a bus stop in Turin following a wrong turn.

[36] On 16 February 2017, Cáceres joined Premier League club Southampton as a free agent, signing an initial contract lasting until the end of the season.

[37][38] Ten days later he was included in a matchday squad for the first time, remaining an unused substitute in the final of the EFL Cup, a 3–2 loss to Manchester United.

He joined Verona instead as a result, although rumours circulated in the media linking him with a possible move to Lazio in January as there were no restrictions impeding the transfer of non-EU players between Italian clubs.

[54] Cáceres moved to Cagliari on a one-year contract on 1 September 2021, where he shared teams with national teammates Diego Godín and Nahitan Nández.

[64][65] In 2010, he was selected by manager Óscar Tabárez for his list of 23 players for that year's FIFA World Cup,[66] as back-up to Porto's Jorge Fucile at right-back[67] and taking part in the semi-finals against the Netherlands and the third-place match against Germany (both 3–2 losses).

In the third-place match against Italy, his penalty was saved by Juventus teammate Gianluigi Buffon as the opposition won the shootout by 3–2 after a 2–2 deadlock following extra time.

[75] He was also a member of the squad that took part at the 2014 World Cup,[76] featuring four times in the tournament to help the nation reach the last-16 phase, where they suffered a 2–0 defeat to Colombia at the Maracanã Stadium on 28 June.

[85][86] Cáceres's primary position is that of a central defender, but he can also operate as a left or right-back, being noted for his pace, strength, tackling and aerial ability.