Martino was assigned as head coach of the Paraguayan national football team in February 2007, replacing Uruguayan Anibal “Maño” Ruiz. His knowledge and success while coaching Paraguayan clubs were the parameters that positioned him as the best option for the job (other candidates were Nery Pumpido and Miguel Ángel Russo). Previously, Martino had won the Paraguayan league four times from 2002 till 2006.

In 2008, Martino was linked for vacant managerial position of Iran Pro League side Steel Azin but the deal was cancelled due to personal reasons. On 5 July 2010, Martino announced that he would be stepping down as Paraguay coach on their return from the 2010 FIFA World Cup in which he led Paraguay to quarter-finals. Martino confirmed that with his four-year contract expiring, he would not be extending his spell in charge of the national side. However, on 10 July 2010, Martino agreed to stay on as Paraguay coach until after the 2011 Copa America, in which Paraguay were runners-up after losing to Uruguay in the final.

On 22 July 2013, Martino was confirmed as manager of Spanish club Barcelona to replace Tito Vilanova who resigned three days earlier. He signed a two-year deal at Barcelona. His first competitive game in charge of Barça was on 18 August 2013 against Levante, a game which Barcelona won 7–0 on the opening weekend of the 2013–14 La Liga season. On 26 October 2013, Martino won 2–1 against rivals Real Madrid at the Camp Nou, winning his first Clásico as a Barcelona manager. Three days later, Barcelona went on to win 0–3 at Celta de Vigo and Martino became the first coach in Barcelona history to not lose a game in their first 16 matches. On 26 November, Martino’s unbeaten start as Barcelona coach came to an end after his 21st game in charge, as Barcelona lost 2–1 away at Ajax in the 2013–14 UEFA Champions League. After conceding the 2013–14 La Liga title on the last day of the season to Atlético Madrid, Martino announced he was to leave his role after just one year in charge during which he did not manage to win any major trophy except the Spanish Super Cup.

On 12 August 2014, Martino was introduced as the new manager for the Argentine national team, succeeding Alejandro Sabella who took the side into the final against Germany at the World Cup in Brazil. In the 2015 Copa América, he reached the final, in which Argentina were runners-up after losing to hosts Chile on penalties. They also finished as runners-up in the Copa América Centenario Final on 26 June 2016 against Chile, again losing on penalties. On 5 July 2016, Martino resigned.

After departing from Argentina, Martino was announced as Major League Soccer expansion team Atlanta United’s inaugural season manager on 27 September 2016. On 23 October 2018, Martino announced that he would not renew his contract with Atlanta United following the conclusion of the 2018 MLS season, citing personal reasons. He was expected to sign with the Mexico national team. Atlanta defeated the Portland Timbers in the MLS Cup, winning their first league title in Martino’s last match with the club.

On 7 January 2019, Martino was announced as head coach of the Mexico national team in his return to international management since leaving Argentina in May 2016. On 22 March, Martino won his first match with Mexico with a 3–1 win over Chile in a friendly. Later in the same year, Martino and Mexico won the CONCACAF Gold Cup over rivals the United States in a 1–0 victory, his first national title.