Muguruza won all her four matches at the Fed Cup in 2016. At the Italian Open, she defeated world No. 10 Timea Bacsinszky and then in semifinal lost to eventual runner–up Madison Keys. One of the most significant result of Muguruza happened at the French Open. She defeated World No. 1 Serena Williams in order to get to the first Grand Slam title. She started the tournament with one lost set against Anna Karolína Schmiedlová in the first round, after that she did not drop a single set on her way to the trophy. During the Summer, she played at the Olympic Games, where she won two matches, before she lost to eventual gold medalist Monica Puig in the third-round match. Later, she reached the semifinals of the Cincinnati Open, losing to Karolína Plíšková. Muguruza spend all weeks of 2016 inside the top 10.