Resilience as a strength-based notion, measured across cultures, age groups, and sub-populations, contributes to understanding health and well-being. Yet, there is limited evidence of how the construct performs in resource-limited countries. We explored the psychometric properties of the CYRM-28 and validated the scale with adolescents living with HIV (ALHIV), a key sub-population. The participants included members of an advisory panel and 406 ALHIV, aged 15–19 years, attending an antiretroviral therapy and teen-club clinic in Blantyre, Malawi. This study employed a mixed-method study using an exploratory sequential design. The advisory panel discussed the CYRM-28, and select ALHIV then translated it into Chichewa, pilot-tested it using cognitive interviews, and back-translated it for clarity and appropriateness. The resultant CYRM-28 was tested using a survey with purposefully selected ALHIV. The overall median score was 123, with an interquartile range of 110–130. Minimum and maximum scores were 53 and 140. Cronbach’s alpha of 0.863 and Kaiser–Meyer–Olkin measure (0.866) confirmed internal consistency and the sample size adequacy, respectively. Bartlett’s tests of sphericity (p < 0.001) informed factor analysis. Exploratory factor analysis determined possible dimensions of resilience and the sub-scales. The confirmatory factor analysis (CFA) confirmed the construct validity and supported a three-factor model consistent with the conceptualization of resilience as a multi-dimensional construct. Structural equation modeling was applied to perform CFA to measure model of resilience. Multiple fit indices showed a good fit for the model. The CYRM-28 has good internal consistency, test and re-test reliability, and moderate convergent validity which render it useful as a self-report resilience measure to inform and evaluate interventions for the health and well-being of adolescents in Malawi.