Caregiving self-efficacy is a major factor in mitigating mental health issues and improving care satisfaction and care behavior in caregivers. This study investigated gratitude and sense of meaning in life’s influence on caregiving self-efficacy of family caregivers of persons with mental illness. We collected data from 142 family caregivers using the Korean self-reporting scale of gratitude, meaning in life, and caregiving self-efficacy. Data analysis was performed using hierarchical regression analysis. Gratitude and the presence of meaning were significant factors in boosting caregiving self-efficacy. Therefore, these factors must be promoted to enhance the caregiving self-efficacy of family caregivers of persons with mental illness.