Background: Effective interventions to promote well-being at work are required to reduce the prevalence and consequences of stress and burnout especially during the COVID-19 pandemic. This study determined the effects of mindful coloring on perceived stress levels, mental well-being, burnout, and state and trait mindfulness levels for nurses during COVID-19.Methods: This was a single-center, two-armed, parallel, superiority, blinded randomized controlled trial. Seventy-seven participants were randomly allocated (by computer-generated sequence) to either mindful coloring (n = 39) or waitlist control groups (n = 38). Twenty-seven nurses in the mindful coloring group and 32 in the control group were included in the full compliance per protocol analysis. The mindful coloring intervention included participants viewing a 3-minutes instructional video and coloring mandalas for at least 5 working days or 100 minutes in total during a 10-day period. Participants in both groups completed the Perceived Stress Scale (total score 0-40), short Warwick-Edinburgh Mental Well-being Scale (total score 7-35), Maslach Burnout Inventory-Human Services Survey for Medical Personnel (3 subscales), Five Facets Mindfulness Questionnaire-Short Form (total score 24-120) and Mindful Attention Awareness Scale-State version (total score 0-30) instruments. The primary outcome was the perceived stress level.Results: Baseline prevalence of moderate to high perceived stress level was high (79.2%). There was a large mindful coloring effect on reducing mean perceived stress levels (Mean difference [MD] in change between groups −3.0, 95% CI: −5.0 to −1.00; Cohen's d = 0.80). Mindful coloring may lead to a small improvement in mental well-being level (P = .08), with an improvement found in the intervention group (MD 0.9, 95% CI 0.0-1.8, P = .04) through enhanced state mindfulness (P < .001). There were no effects on changing burnout subscales or trait mindfulness levels. No adverse reactions were reported. Conclusion:Coloring mandalas may be an effective low-cost brief intervention to reduce perceived stress levels through enhancing state mindfulness and it may promote mental well-being. Hospitals may promote or provide mindful coloring as a selfcare and stress-relief practice for nurses during their off hours or work breaks.