Background: Social distancing and stay-at-home orders are critical interventions to slow down person-to-person transmission of COVID-19. While these societal changes help contain the pandemic, they also have unintended negative consequences, including anxiety and depression. We developed StayWell, a daily skills-based SMS text messaging program, to mitigate COVID-19–related depression and anxiety symptoms among people who speak English and Spanish in the United States. Objective: This paper describes the changes in StayWell participants’ anxiety and depression levels after 60 days of exposure to skills-based SMS text messages. Methods: We used self-administered, empirically supported web-based questionnaires to assess the demographic and clinical characteristics of StayWell participants. Anxiety and depression were measured using the 2-item Generalized Anxiety Disorder (GAD-2) scale and the 8-item Patient Health Questionnaire-8 (PHQ-8) scale at baseline and 60-day timepoints. We used 2-tailed paired t tests to detect changes in PHQ-8 and GAD-2 scores from baseline to follow-up measured 60 days later. Results: The analytic sample includes 193 participants who completed both the baseline and 60-day exit questionnaires. At the 60-day time point, there were significant reductions in both PHQ-8 and GAD-2 scores from baseline. We found an average reduction of –1.72 (95% CI –2.35 to –1.09) in PHQ-8 scores and –0.48 (95% CI –0.71 to –0.25) in GAD-2 scores. These improvements translated to an 18.5% and 17.2% reduction in mean PHQ-8 and GAD-2 scores, respectively. Conclusions: StayWell is an accessible, low-intensity population-level mental health intervention. Participation in StayWell focused on COVID-19 mental health coping skills and was related to improved depression and anxiety symptoms. In addition to improvements in outcomes, we found high levels of engagement during the 60-day intervention period. Text messaging interventions could serve as an important public health tool for disseminating strategies to manage mental health.@en