In the face of the growing mental health crisis affecting young people, especially post-pandemic, effective strategies for the promotion and prevention of wellness in educational settings are imperative. Self-affirming interventions are strategies capable of mitigating this negative impact and promoting well-being in students. This study aims to provide evidence of the effectiveness of these interventions on health-related quality of life and academic performance in Chilean educational contexts. A two-wave quasi-experimental design was used, with a quasi-experimental group and a quasi-control group, both composed of elementary school students from educational establishments in northern Chile. To evaluate the impact of these interventions, 2 self-report measures were used, the KIDSCREEN-52 Index and the annual grade point average. Regarding HRQOL, the results revealed significant baseline differences between the quasi-experimental and quasi-control groups, which were reduced after the intervention, with greater changes being observed in the quasi-experimental group. Regarding performance, significant differences were observed between the quasi-experimental and quasi-control groups after the intervention, with higher scores in the quasi-experimental group. Self-affirmation interventions have proven to be a useful, effective and practical strategy to improve various indicators of health-related quality of life and performance in educational settings, especially after a health crisis.