His performances earned him a transfer to defending Serie A Champions Juventus, where he won consecutive league titles during his first two seasons with the team.

Isla has earned over 140 caps for Chile since his debut in 2007, and represented the nation in two FIFA World Cups (in 2010 and 2014) as well as six Copa América tournaments (in 2011, 2015, 2016, 2019, 2021 and 2024), winning the 2015 and 2016 editions.

Isla had a notable performance during the summer of 2007 in the 2007 FIFA U-20 World Cup in Canada and was thereafter signed by Udinese of the Serie A in Italy on a five-year contract.

After the departure of Simone Pepe, Isla often played as a right wing-back in a 3–5–2 formation during Udinese's 2010–11 Serie A campaign, due to a long-term injury to Dušan Basta.

In that season, he was instrumental in helping Udinese finish fourth, thus gaining qualification to the 2011–12 UEFA Champions League play-off round.

On 15 June 2012, Juventus announced Isla's arrival to a medical ahead of a prospective move to join the team for the upcoming 2012–13 season.

[15] After settling into life in West London, Isla signaled his intention to take up the option of making the loan permanent at the end of the season.

[21] Isla debuted for Flamengo on 30 August 2020 as a halftime substitute in a Campeonato Brasileiro Série A 1–0 win over Santos at Vila Belmiro.

[24] After ending his contract with Universidad Católica, in August 2023 Isla joined Argentine Primera División side Independiente,[25] where he became one of the leaders in the new team of Carlos Tévez.

In the quarterfinal game versus Nigeria, Isla played defender, midfield, and forward due to a number of injuries to other squad members.

This tournament and his performance in it led Isla to be transferred to Serie A team Udinese before his professional debut in the Chilean league, a very rare occurrence.

New Chilean coach Marcelo Bielsa called Isla up at the age of 19 for his first full Chile senior squad international cap in September 2007 in a friendly against Switzerland versus his club-mate Gökhan Inler.