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Background Social isolation and the impact on mental health is a major concern during COVID-19. Trait equanimity is expected to protect individuals from psychological distress associated with social isolation. The aim of this study is to examine the link between social isolation and psychological distress via the mediator equanimity. It was hypothesised that objective (few social contacts) and perceived social isolation (loneliness) would predict psychological distress and that equanimity would mediate these relationships. Methods Five hundred and seventy-eight adult United States participants were recruited and completed measures of objective social isolation and perceived social isolation (De Jong Gierveld Social Isolation scale), trait equanimity (Phenomenological Experience of Meditative Equanimity Scale), and psychological distress (Depression, Anxiety, and Stress Scale, Short Form, DASS-21). Results Objective social isolation negatively predicted psychological distress, but equanimity did not mediate this relationship. Perceived social isolation positively predicted psychological distress and equanimity mediated this relationship. Limitations This study is limited by its cross-sectional and self-report design and by a United States sample, which may affect the generalisability of findings. Conclusions Rather than a lack of social contact it is the “perceived” nature of isolation that is related to psychological distress and this relationship indirectly operates through trait equanimity. Individuals high in trait equanimity may be better protected from the impact of perceived social isolation. Clinical interventions can be adapted to include equanimity skills to mitigate perceived social isolation for individuals and reduce adverse outcomes.