He played his first tournament since undergoing wrist surgery in the 2016 Delray Beach Open. In his first competitive match in almost a year, del Potro defeated Denis Kudla in two sets. He followed this up with a straight sets win over Australian John-Patrick Smith. He defeated Jérémy Chardy in two sets in the quarterfinal, reaching his first semifinal since 2014; which he lost to eventual champion Sam Querrey. He returned to Indian Wells, competing in the first round, winning against Tim Smyczek in two sets. He lost in the next round to Tomas Berdych in straight sets. His next tournament was the Miami Open. He won his first match against countryman Guido Pella in two sets. He was set to play Roger Federer for the first time in more than two years, but just hours before the match Federer withdrew due to a stomach virus. He then played lucky loser and countryman Horacio Zeballos and lost in straight sets. He then competed in his first clay-court tournament since 2013 at the BMW Open. He won his first clay-court match in three years against Dustin Brown, beating him in two sets.