Specific personality traits and poor social support are risk factors for anxiety and depression. Little work, however, has considered the effects of social support and personality on these aspects of psychopathology simultaneously. We examined whether perceived social support mediates the effects of core personality domains on symptoms of anxiety and depression. Measures of personality (based on the Five-Factor Model [FFM]), perceived social support, and symptoms of depression and anxiety were collected in a large Dutch adult population-based sample (n = 555), and, except for depression symptoms, in an independent U.S. adult population-based sample (n = 511). Path modeling was used to test the effects of FFM traits on symptoms of depression and anxiety, with and without the mediation of perceived social support. Social support showed no link to symptoms of anxiety and only modest links to symptoms of depression when controlling for the FFM traits. Neuroticism had the strongest effect on symptoms of both depression and anxiety, with Extraversion also showing links to symptoms of depression. Social support has limited influence on symptoms of depression, and no effects on anxiety, over and above the effects of personality. Links between social support and anxiety/depression may largely reflect influences of Neuroticism and Extraversion.