On 12 August 2021, Hendriks was the first winning pitcher in Iowa during the Field of Dreams game despite blowing a save opportunity when the White Sox were up 7-4 in the top of the ninth. With two outs, Hendriks allowed four runs by giving up back-to-back, two-run home runs to New York Yankees batters Aaron Judge and Giancarlo Stanton to give the Yankees an 8-7 lead. Fortunately for Hendriks, he was still able to get the win due to Tim Anderson hitting a two-run, walk-off home run to give the White Sox a 9-8 win. Overall in 2021, Hendriks appeared in 69 games while recording an American League-leading 38 saves and having a record of 8-3. He also had an ERA of 2.54 in 71 innings and led all MLB relievers in strikeouts with 113. Hendriks won the Mariano Rivera AL Reliever of the Year Award for the second year in a row, becoming the second White Sox pitcher in history to win Reliever of the Year, joining Bobby Thigpen.
