Problematic smartphone use (PSU) has been linked with stress. Higher levels of stress likely increased problematic smartphone use. We investigated relations between stress, fear of missing out, and problematic smartphone use. The aim of the current study was to analyze the mediating role of fear of missing out (FOMO) and smartphone use frequency (SUF) between stress and PSU. We surveyed a broad sample of 2,276 Chinese undergraduate students in July 2019, using the FOMO Scale, Smartphone Addiction Scale-Short Version, Smartphone Use Frequency Scale, and Depression Anxiety Stress Scale-21. The results showed that stress was associated with PSU severity. Gender differences were found in PSU severity. Furthermore, FOMO was positively associated with SUF and PSU severity. Structural equation modeling demonstrated that FOMO acted as a mediator between stress and PSU severity. FOMO and SUF acted as a chain of mediators between stress and PSU severity. SUF did not account for relations between stress and PSU severity. The study indicates that FOMO may be an important variable accounting for why some people with increased stress levels may overuse their smartphones.