Thiem began the 2021 season at the ATP Cup, Austria were defeated in the group stage. Thiem lost his opener to Matteo Berrettini, and was a set up when Benoit Paire had to retire due to injury in his second match. At the Australian Open Thiem reached the fourth round by defeating Nick Kyrgios, coming back from two sets down to win in five sets. In the fourth round he was defeated by Grigor Dimitrov in straight sets. Thiem's next tournament was Doha, where he beat Aslan Karatsev in 3 sets before losing to Roberto Bautista Agut. He then lost in the first round of Dubai to Lloyd Harris. After these losses Thiem took a break to "recharge" and recover from a knee injury. His first tournament back was the Madrid Open, where he reached the semifinals by defeating Marcos Giron, Alex de Minaur and John Isner before losing to Alexander Zverev in straight sets. At the Italian Open, Thiem beat Marton Fucsovics before falling to Lorenzo Sonego in the third round. In Lyon, Thiem lost his opening match to Cameron Norrie. At the French Open, Thiem lost in the first round to Pablo Andújar in five sets, despite being 2 sets up.