Playing in his first Masters Series event since Monte Carlo the previous year, he appeared at the 2010 BNP Paribas Open in Indian Wells. There, he won his first-round match against Stefan Koubek, 6–2, 7–6. In his next-round match, he played 22nd seed Jürgen Melzer and lost 4–6, 1–6. He then entered the 2010 Sony Ericsson Open in Miami as a wildcard entrant. He beat Łukasz Kubot 6–3, 6–2, and 30th seed Viktor Troicki 6–3, 4–6, 6–4, before falling to the fourth seed Rafael Nadal in three sets 7–6, 2–6, 2–6. He entered the 2010 Monte-Carlo Rolex Masters in Monaco, ranked No. 151 in the world, beating Andreas Beck in straight sets, before coming through 3–6, 6–4, 7–6 against World No. 13 Mikhail Youzhny of Russia in the second round. Nalbandian beat Tommy Robredo, before losing in the quarterfinals to the second-ranked Novak Djokovic 2–6, 3–6. Nalbandian withdrew from the 2010 Internazionali BNL d'Italia with a right leg injury. The injury persisted, and he withdrew from the 2010 Mutua Madrileña Madrid Open, the 2010 Roland Garros and the 2010 Wimbledon Championships.