Arriving in Lisbon from Manchester City in the summer of 2020, the Buenos Aires-born centre-back had already built a career at the highest level before becoming one of the defining leaders of the modern Benfica era.

Formed at Vélez Sarsfield, where he made his debut in 2008 and won the 2009 Clausura, Otamendi moved to Europe with FC Porto in 2010, winning three Primeira Liga titles and the 2010/11 UEFA Europa League. Spells at Valencia and Manchester City followed, the latter bringing two Premier League titles, an FA Cup and four League Cups.

At Benfica he wore the captain's armband and made 281 appearances across six seasons, lifting the 2022/23 Primeira Liga, the 2024/25 Taça da Liga and two Supertaças Cândido de Oliveira. In January 2026 he reached 100 UEFA Champions League appearances. He bid farewell to the Estádio da Luz in May 2026 before signing for River Plate.

With Argentina he has collected more than 130 caps, winning the 2022 FIFA World Cup and the Copa América in 2021 and 2024.