This study developed an interpersonal care-based Orff music activity program for children from multicultural families in Republic of Korea. We measured its effects on ego-resilience, peer relationships, happiness, interpersonal care awareness, anxiety, and stress. The participants were 74 children from third to sixth grade attending 10 regional children’s centers in Cheonan-si, Chungcheongnam-do Province, Republic of Korea. They were randomly assigned to 36 experimental groups and 38 control groups. The experimental program was developed based on investigations of human care theory, expressions of care, and Orff music activities. The experiment was conducted twice a week for five weeks in 45 min sessions. Data were collected from June to September 2020. We used questionnaires on ego-resilience, peer relationships, happiness, and interpersonal care awareness to measure the effects, which were analyzed through frequency and descriptive statistics. Anxiety, physiological anxiety, acculturation stress, and physiological stress were measured using Behavior Detection VibraImage System Version 8.1 PRO (VIBRASYSTEM Ltd., Co., Seoul, Republic of Korea). The homogeneity of the variables across groups was examined using the χ² test, t-test, and Fisher’s exact test. The effects were examined using repeated measures variance analysis and independent t-tests. The results showed that the program had significant effects on ego-resilience, peer relationships, happiness, interpersonal care awareness, physiological anxiety, and physiological stress. The findings suggest that interpersonal care nursing can be effective for children from multicultural families, and the program can be used for intervention to improve children’s mental health.