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Psychophysiological stress can affect the cognitive response and effective learning of students during medical simulation practices. This study aimed to explore the effect of psychophysiological stress and socio-emotional competencies on clinical performance during a simulation experience. A pre-test/post-test design was used to assess physiological (blood pressure, heart rate and blood oxygen saturation) and psychological parameters (stress and anxiety) as well as socio-emotional skills (cognitive load, self-efficacy and motivation) in nursing students (n = 40) before and after the simulation of a cardiopulmonary resuscitation practice. Physiological responses showed statistically significant differences between pre-test and post-test conditions for blood pressure and heart rate (p < 0.0001). Moderate and significant correlations were also observed when comparing self-efficacy with stress (r = −0.445, p = 0.004), anxiety (r = −0.467, p = 0.002) and motivation (r = −0.406, p = 0.009) measures. Similarly, cognitive-load dimensions were significantly associated with either physiological (r = −0.335, p = 0.034) or psychological (r = −0.448, p = 0.004) indicators. The analysis of multiple regression models revealed a relationship between the effectiveness of the simulated experience, post-test blood oxygen saturation, heart rate, workload and self-efficacy (R² = 0.490; F (3, 39) = 8.305; p < 0.0001; d = 1.663). Therefore, the evaluation of psychophysiological parameters and socio-emotional skills seems to provide a promising framework for predicting the quality of simulated clinical practices.