Among personality traits, extraversion has received major theoretical and empirical attention as predictor of subjective well-being (SWB), whereas the role of emotional stability-neuroticism has been partially neglected. The present study aims to study the role of neuroticism in the relationship between introversion-extraversion and SWB. In particular, we explored if the trait of neuroticism moderates the relationships between introversion-extraversion and SWB dimensions (Satisfaction with life, Mastery, Vigour, Social Cheerfulness), directly and by mediation of self-esteem. Indeed, previous studies have suggested that self-esteem is positively associated with high extraversion and low neuroticism and that it positively mediates the relationship between SWB and personality traits in adolescents. For this purpose, a sample of high school students (N = 1173) completed the Oxford Happiness Inventory, the Rosenberg Self-Esteem Scale and the Big Five Questionnaire. In a latent variable model, we examined the interaction effects (direct and indirect) of extraversion and neuroticism on SWB dimensions. Our results showed that the nature of differences between introverts and extraverts on SWB could be related to the level of neuroticism in relation to Satisfaction with life. Moreover, self-esteem mediated the relationship between personality traits and SWB. In particular, mediated moderation effect analysis showed that self-esteem mediates completely the relationship between the interaction term (extraversion x neuroticism) and Mastery, and partially the relationship with Satisfaction with life. Moreover, moderated mediation effect analysis showed that high levels of neuroticism moderate the effect of extraversion on Satisfaction with life and Mastery through the mediation of self-esteem. In conclusion, our results suggest that although extraversion has a cardinal role on SWB dimensions related to Vigour and Social Cheerfulness, neuroticism and the mediating role of self-esteem should more properly considered in relation to Satisfaction with life and Mastery.