Ranked 43 at the US Open, Vinci won her first three rounds defeating Vania King, Denisa Allertová, and Mariana Duque Mariño. Vinci then reached her third US Open quarterfinal in four years after Eugenie Bouchard withdrew a few hours before their fourth-round match after she slipped and hit her head in the locker room. In the quarterfinals, Vinci defeated Kristina Mladenovic 6–3, 5–7, 6–4 to reach the semifinals. At 32, Vinci became the oldest first-time Grand Slam semifinalist in the Open Era. She then dispatched defending champion Serena Williams in three sets en route to her first Grand Slam final, while also ending Williams' attempt at a calendar-year Grand Slam. Vinci was ranked 42 places lower than Williams at that time. Numerous major media outlets reported about Vinci's win over Williams being one of the biggest upsets in tennis history. She lost to Flavia Pennetta in the final in straight sets in what was the first all-Italian Grand Slam final in the Open Era. By virtue of her run to the final in New York, Vinci returned to the top 20 for the first time since June 2014.