Exploring the effect of certain factors on problematic smartphone use (PSU) and the mechanism of these effects may help researchers understand the antecedents of PSU and propose targeted interventions. Accordingly, the current study tested the mediating role of self-control and the moderating role of gender in the relationship between neuroticism and PSU. A sample of 768 Chinese smartphone users (439 female, 329 male) aged 14–37 years (M = 22.5, SD = 3.27) completed questionnaires on neuroticism, self-control, nomophobia, and mobile phone addiction. The results showed that females reported significantly higher PSU than males. In addition, for females, self-control partially mediated the relationship between neuroticism and PSU, while for males, neuroticism had only a direct effect on PSU. The findings shed light on the effect of neuroticism on PSU and highlight the importance of gender in this effect.