Background: COVID-19 incidence in Indonesia was high among adolescents, but vaccine acceptance remains low. The unequal geographical distribution of the health workforce and health facilities in Indonesia, including a lower number of health workers and facilities in Maluku-Papua, resulted in a low rate of vaccine acceptance. Knowledge, attitude, belief in the vaccine, comorbidity, congenital status are related to vaccine adherence, but mediation analysis of factors remains lacking. We aimed to analyze path analysis of knowledge, congenital, comorbidity, belief, and attitude to COVID-19 vaccine adherence among adolescents in Indonesia, Maluku-Papua Island, and Java Island. Method: A nationwide cross-sectional study was undertaken among 7604 adolescents. A path analysis to investigate mediating effects between variables combined with bootstrapping was utilized to determine statistical significance. Result: Knowledge, congenital status, comorbidity, belief, and attitude were significantly positively associated with COVID-19 vaccine adherence among adolescents in Maluku-Papua Island (p < 0.01; n = 4761), Java Island (p < 0.01; n = 1573), and Indonesia (p < 0.05; n = 7604). Congenital status, belief, and attitude negatively mediated the relationship between knowledge of and adherence to COVID-19 vaccine (p < 0.01) in Indonesia and among the subgroup on Maluku-Papua Island (p < 0.01), but a positive mediation (p = 0.04) in our subgroup analysis of Java Island. Comorbidity status, belief, and attitude negatively mediated relationship between knowledge and adherence to COVID-19 vaccine in Indonesia (p ≤0.01) and Maluku-Papua (p = 0.00), but no mediation role was found in Java Island (p = 0.58). Conclusion: Comorbidity, congenital illness status, belief in and attitude to COVID-19 vaccine negatively mediated the relationship between knowledge of and adherence to COVID-19 vaccine among adolescents in Indonesia and our sub-group on Maluku-Papua Island but not on Java Island. Practical implication: Massive improvement in healthcare facility equality plays an important role in Indonesia gaining COVID-19 vaccine adherence.