Affective responses during stressful, high-stakes situations can play an important role in shaping performance. For example, feeling shaky and nervous at a job interview can undermine performance, whereas feeling excited during that same interview can optimize performance. Thus, affect regulation—the way people influence their affective responses—might play a key role in determining high-stakes outcomes. To test this idea, we adapted a synergistic mindsets intervention (SMI) (Yeager et al . 2022 Nature 607 , 512–520 (doi: 10.1038/s41586-022-04907-7 )) to a high-stakes esports context. Our approach was motivated by the idea that (i) mindsets both about situations and one’s stress responses to situations can be shaped to help optimize stress responses, and (ii) challenge versus threat stress responses will be associated with improved outcomes. After a baseline performance task, we randomly assigned gamers ( n = 300) either to SMI or a control condition in which they learned brain facts. After two weeks of daily gaming, gamers competed in a cash-prize tournament. We measured affective experiences before the matches and cardiovascular responses before and throughout the matches. Contrary to predictions, gamers did not experience negative affect (including feeling stressed), thus limiting the capacity for the intervention to regulate physiological responses and optimize performance. Compared with the control participants, synergistic mindsets participants did not show greater challenge responses or improved performance outcomes. Though our adaptation of Yeager et al .’s SMI did not optimize esports performance, our findings point to important considerations regarding the suitability of an intervention such as this to different performance contexts of varying degrees of stressfulness.