Pizzi earned 22 caps for Spain and scored eight goals, his debut coming on 30 November 1994 in a 2–0 friendly win with Finland. In the following year, on 20 September, he helped beat his country of birth Argentina 2–1, in an exhibition game played in Madrid.

With Barcelona, Pizzi won the Spanish Supercup in 1996, the UEFA Super Cup and Spanish Cup in 1997, conquering the latter again in the following year while also winning his only league title. Arguably, his most memorable moment was the decisive goal in the 5–4 home win over Atlético Madrid in the domestic cup’s quarter-finals second leg, after the Blaugrana trailed 0–3 at half-time.

On 13 April 2006, Pizzi became the coach of Club Deportivo Universidad de San Martín de Porres in the Peruvian top level. He returned to his country of birth five years later, working with Rosario Central and San Lorenzo de Almagro and winning the 2013 Inicial with the latter.

On 26 December 2013, Pizzi returned to Valencia after 20 years, being appointed manager. His first game in charge was on 4 January of the following year, a 2–0 derby home win over Levante UD.

Pizzi was sacked on 2 July 2014, after new owner Peter Lim took over. It was the first time in 16 years that Valencia had failed to qualify for Europe, after an eighth-place finish.

On 29 January 2016, after one year at the helm of Club León in the Liga MX, Pizzi replaced Jorge Sampaoli at the Chile national side. He took the nation to victory in the Copa América Centenario in the United States, notably disposing of Mexico 7–0 in the last-eight stage and defeating Argentina on penalties in the decisive match.

On 28 November 2017, Pizzi was appointed to manage Saudi Arabia, becoming the third man to hold the position in as many months. The team’s run at the 2018 World Cup ended after the first three games (one win and two losses); On 21 January 2019, after round-of-16 elimination at the AFC Asian Cup and not having been approached by the Saudi Arabian Football Federation regarding the renewal of his contract, he resigned.

Pizzi returned to San Lorenzo in June 2019, six years after his first managerial spell. On 31 October, he was dismissed due to poor results.