We investigated the relationship between personality and quality of life (QoL) considering emotion regulation and self-efficacy beliefs as mediating factors. A total of 409 participants from the French-speaking regions of Switzerland and from France completed questionnaires on personality, emotion regulation, self-efficacy beliefs, and QoL. Our findings revealed that specific personality traits have significant direct and indirect effects on QoL, mediated by emotion regulation and self-efficacy. Particularly, neuroticism was strongly and negatively related to emotion regulation and QoL, but not significantly linked to self-efficacy, whereas extraversion and conscientiousness were positively associated with all variables. This is the first study to demonstrate that both emotion regulation and self-efficacy are important mechanisms that link specific personality traits to QoL, suggesting that they channel and modulate the personality effects. However, more work is needed to understand these relationships in more detail (e.g., how the personality traits concurrently influence each other as well as emotion regulation and self-efficacy).