This study investigated the efficacy of a culturally modified resilience education program on Japanese adolescents’ well-being from a differential susceptibility perspective. First, a culturally modified resilience education intervention was developed by employing the SPARK resilience program and implemented with 407 Japanese high school students in Tokyo (age = 15–16, M = 192, F = 215). To test intervention efficacy, students’ level of resilience, self-esteem, self-efficacy, and depression were measured pre-, post-, and three months after intervention. Additionally, sensory processing sensitivity, using the Japanese version of the Highly Sensitive Child Scale for Adolescence, was measured as an index of individual sensitivity. Analysis of variance was used to examine the baseline differences and interaction effects of students’ gender and level of sensory processing sensitivity. Latent growth curve models were used to assess the overall effects of the intervention and change over time. Results indicated that the intervention was effective in enhancing students’ overall self-efficacy; and that highly sensitive students, who scored significantly lower in well-being than their counterparts at baseline, responded more positively to the intervention, and had a greater reduction in depression and promotion of self-esteem. These findings provided unique evidence in line with the differential susceptibility perspective and useful implications to develop personalized treatment interventions for adolescents in different cultural contexts.