On 23 August 2010, Otamendi was transferred to Portuguese side FC Porto on a €4 million fee, signing a five-year contract. Vélez also retained 50% of his registration rights, with the player having a pre-set price of another €4 million to be met by Porto prior to September 2011. He netted in his first match, a 2–0 home victory over S.C. Olhanense, finishing his first season with 15 appearances and five goals (notably both in a 2–0 away win against S.C. Braga) as the northerners won the Primeira Liga championship.
During the 2010 FIFA World Cup qualifying campaign, Otamendi played as a centre back alongside Martín Demichelis against Ecuador (0–2 away loss), partnered former Vélez teammate Domínguez against Brazil in a 1–3 home defeat and appeared as a right back in a 1–0 win in Uruguay which sealed the country's qualification to South Africa. On 19 May 2010 he was confirmed as part of the 23-men squad for the final stages, featuring in the starting eleven for the final group stage game against Greece; on the press conference after the match, Maradona said that, in his opinion, he was the best player on the field.