The present study examined the prospective direct and interactive effects of personality (neuroticism, extraversion) and experiencing changes in friendships during the pandemic on symptoms of stress, anxiety, and depression. A sample of patients (N = 77) at an outpatient treatment clinic who had received a diagnostic assessment in the 6months prior to the COVID-19 lockdown was re-contacted during the pandemic (May-June 2020) and completed a survey assessing stressors and symptoms of internalizing psychopathology. Neuroticism had main effects on anxiety, whereas experiencing changes in friendships had main effects on stress and depression. Extraversion did not have main effects on stress, depression, or anxiety. The relationship between experiencing changes in friendships and stress and anxiety was moderated by extraversion, such that the strength of the relationship between changes in friendships and stress and anxiety waned as the level of extraversion increased. Neuroticism was not a moderator of the association between changes in friendships and emotional disorder symptoms. These results suggest that higher levels of extraversion may protect against symptoms of stress reactivity and anxiety that are associated with COVID-related changes in friendships, while neuroticism may have limited prospective associations with symptoms during the pandemic. The online version of this article contains supplementary material available 10.1007/s10608-023-10364-x.