In Argentina's opening match of the Copa América Centenario on 6 June 2016, a rematch of the previous tournament's final against defending champions Chile, Di María scored the opening goal of the match, and later assisted Éver Banega's goal in a 2–1 win. Di María dedicated the goal to his grandmother, who had recently died. In his nation's second group match, against Panama on 10 June, he assisted Nicolás Otamendi's opening goal, but was later forced off due to injury. Argentina won the match 5–0. He missed the rest of the tournament due to injury as Argentina reached the Copa América final for the second consecutive time, once again losing out to Chile on penalties, following a 0–0 draw.