Background. The aim of this research was to analyze whether the personality factors included in the Big Five model differentially predict the self-regulation and affective states of university students and health. Methods. A total of 637 students completed validated self-report questionnaires. Using an ex post facto design, we conducted linear regression and structural prediction analyses. Results The findings showed that model factors were differential predictors of both self-regulation and affective states. Self-regulation and affective states, in turn, jointly predict emotional performance while learning and even student health. These results allow us to understand, through a holistic predictive model, the differential predictive relationships of all the factors: conscientiousness and extraversion were predictors regulating positive emotionality and health; the openness to experience factor was non-regulating; nonregulating; and agreeableness and neuroticism were dysregulating, hence precursors of negative emotionality and poorer student health. Conclusions. These results are important because they allow us to infer implications for guidance and psychological health at university.