In the Italian Open, he was upset by Fabio Fognini in the second round. He claimed his second title of the year at the Lyon Open defeating home favorite Gilles Simon in the final. At the French Open, he was able to reach his first slam final and faced Nadal, but lost in straight sets. At the grass season, Thiem suffered back-to-back loses in the second round of the Gerry Weber Open to Yuichi Sugita and the first round of Wimbledon against Marcos Baghdatis due to a back injury. He then went on a three match losing streak which began with a quarterfinal loss at the German Open to Nicolás Jarry and first round loses at the Generali Open Kitzbühel to Martin Kližan and Rogers Cup to Tsitsipas. At the US Open, Thiem was able to reach the quarterfinals of non-clay slam for the first time but lost to Nadal in a fifth set tiebreak, despite winning the first set in a bagel. He then claimed his third title of the year at the St. Petersburg Open defeating Kližan in the final in two quick sets. At the Shanghai Rolex Masters, he was upset by Matthew Ebden in the second round in a third set tiebreak. At the Erste Bank Open, he reached the quarterfinals losing to Kei Nishikori. At the Rolex Paris Masters, he reached his first semi-final at a Masters tournament on a hard court, but lost to Karen Khachanov. On November 3, following Del Potro's withdrawal from the event, Kei Nishikori was announced as his replacement. Kei Nishikori returned after a 5-month injury layoff and started his 2018 season by playing at the American challenger tour events. At Oracle Challenger Series he lost in the first round against American qualifier Dennis Novikov. Nishikori went on to win his sixth ATP Challenger career titles at the RBC Tennis Championships, by defeating Mackenzie McDonald in the final. Nishikori made his return to the ATP Tour competition (since August 2017 Montreal) at the inaugural ATP 250 Tournament in New York, where he reached the semifinals before losing to Kevin Anderson. He was unseeded at the Abierto Mexicano Telcel and lost against Denis Shapovalov in the first round. At the Miami Masters, he lost in the third round to Juan Martín del Potro. In the clay season, Nishikori entered the Monte-Carlo Rolex Masters, where he reached his 4th career Masters 1000 finals, before losing to Rafael Nadal in straight sets in the finals.