Positive levels of global life satisfaction are associated with a broad range of positive personal, psychological, and social outcomes both in the present and future. However, for adolescents, little is known about the underlying personal characteristics that predict global life satisfaction. Thus, the aim of the study was to investigate the relationship between personality traits, self-esteem, self-efficacy, and global life satisfaction in a sample of 437 Swiss adolescents attending the second last year of compulsory school. Results have shown that conscientiousness, neuroticism, extraversion, self-esteem, and self-efficacy are significantly associated with global life satisfaction. Moreover, self-esteem seems to be a mediator of the relationship between personality traits and global life satisfaction, suggesting that it might be considered as a process variable regulating behaviors, feelings, and thoughts that are related to personality dimensions.