Although many people affected by COVID-19 suffer from some form of psychological distress, access to proper treatment or psychosocial interventions has been limited. This study aimed to examine the feasibility and preliminary effects of a therapeutic gardening program conducted during the COVID-19 pandemic. The program consisted of 30 sessions and was conducted at 10 nationwide sites in Korea from June to November 2021. Mental health and well-being were assessed using the Mental Health Screening Tool for Depressive Disorders, Mental Health Screening Tool for Anxiety Disorders, Engagement in Daily Activity Scale, brief version of World Health Organization Quality of Life, and Mindful Attention Awareness Scale. Cohen’s d value was calculated for the effect size, and a multilevel analysis was used to determine the longitudinal effects of therapeutic gardening. The effect sizes for depression, anxiety, daily activities, quality of life, and mindfulness were 0.84, 0.72, 0.61, 0.64, and 0.40, respectively. Multilevel analyses showed that all five mental health variables improved significantly over time as the therapeutic gardening program progressed. Therapeutic gardening is promising and applicable as a nature-based intervention to improve the mental health of individuals experiencing psychological distress especially in the COVID-19 pandemic.