Life events, such as the Coronavirus disease 2019 (COVID-19) pandemic, elicit increases in psychological stress and symptoms of anxiety and depression. In turn, these outcomes have negative implications for mental health. Emotion regulation strategies and prior adversity may moderate the degree to which life events affect outcomes that are linked to mental health. The purpose of the current study was to evaluate whether childhood adversity and emotion regulation strategy use interactively informed changes in outcomes linked to mental health following the onset of the pandemic in American Indian (AI) adults. AI adults (N = 210) reported levels of childhood adversity, emotion regulation strategy use, symptoms of anxiety and depression, and psychological stress 1 month prior to the onset of the COVID-19 pandemic. One month following the declaration of the pandemic, they reported on their stress, symptoms of anxiety and depression once again. The interaction between expressive suppression and childhood adversity predicted changes in psychological stress and symptoms of depression (B = .26, t(198) = 4.43 p < .001, R2 change = .06) and (B = .23 t(199) = 4.14, p < .001, R2 change = .05) respectively. The findings indicate that expressive suppression may be a maladaptive emotion regulation strategy for AI adults who experienced high levels of childhood adversity. This work represents a first step in understanding the role of emotion regulation strategy use in predicting mental health-relevant outcomes in the context of a life event, in a community that is disproportionately affected by chronic mental health conditions.