Background: Current literature lacks evidence concerning how problematic social media use associates with mental health. To address the gap, the present study used mediation models to examine whether generalized trust and perceived social support (PSS) are potential mediators in the relationship between problematic social media use and mental health. Methods: The sample comprised Iranian adults (n = 1073; 614 females). The participants completed a number of scales to assess problematic social media use (Bergen Social Media Addiction Scale), generalized trust (Generalized Trust Scale), PSS (Multidimensional Scale of Perceived Social Support, happiness (Oxford Happiness Questionnaire Short Form), depression and anxiety (Hospital Anxiety and Depression Scale), and mental quality of life (Short Form-12). Results: Problematic social media use had negative effects on happiness and mental quality of life via the mediators of generalized trust (bootstrapping SE = 0.017; effect = −0.041; 95% CI = −0.079, −0.012) and PSS (bootstrapping SE = 0.023; effect = −0.163; 95% CI = −0.211, −0.119). Problematic social media use had positive effects on anxiety and depression via the mediators of generalized trust (bootstrapping SE = 0.022; effect = 0.064; 95% CI = 0.026, 0.113) and PSS (bootstrapping SE = 0.024; effect = 0.052; 95% CI = 0.009, 0.102). Conclusions: Problematic social media use, generalized trust and PSS are important factors for an individual's mental health. Health-care providers may want to assist individuals regardless of having mental health problems in reducing their problematic social media use and improving their generalized trust and social support.