Background <p>Social comparison orientation, fear of negative evaluation, and social interaction anxiety are key psychological factors that can affect nursing students’ well-being. This study investigates the role of cognitive flexibility as a moderator and mediator in the relationship between social comparison orientation, fear of negative evaluation, and social interaction anxiety.</p> Methods <p>This is a cross-sectional observational study. A total of 198 nursing students from two universities in South Korea participated in this study. Data were collected using self-reported questionnaires between November 1 and December 2, 2024. The data were analyzed using SPSS/WIN 26.0, employing independent t-tests, one-way analysis of variance, Pearson’s correlation coefficients, and Hayes’s PROCESS macro methods (Models 4 and 7) for testing moderated mediation.</p> Results <p>Social comparison orientation significantly positively predicted fear of negative evaluation (B = 0.471, <i>p</i> &lt; .001), but had no significant direct effect on social interaction anxiety. Fear of negative evaluation, however, had a significant positive effect on social interaction anxiety (B = 0.682, <i>p</i> &lt; .001). The interaction between social comparison orientation and cognitive flexibility was statistically significant (B = 0.180, <i>p</i> = .045). Furthermore, cognitive flexibility significantly moderated the mediation effect between social comparison orientation and fear of negative evaluation (B = 0.123, 95% CI [0.023–0.246]).</p> Conclusions <p>The findings suggest that cognitive flexibility plays a critical role in moderating and mediating the relationships among social comparison orientation, fear of negative evaluation, and social interaction anxiety. These results highlight the importance of enhancing cognitive flexibility to reduce anxiety and improve social interactions in nursing students.</p>