Background: COVID-19 vaccination of minors is crucial for global pandemic control, especially among indigenous populations, who are often more vulnerable due to limited healthcare resources and communal living settings. Objectives: To assess the immunogenicity responses of the BNT162b2 vaccine in immunized Brazilian indigenous adolescents. Methods: A cohort study was conducted with indigenous adolescents aged 12 to 18 years residing in the largest peri-urban indigenous region in Brazil. SARS-CoV-2-specific immune responses were analyzed before (D1) and after (D2) completion of the vaccination schedule. Demographic data were collected using a questionnaire. Results: Of the 129 adolescents invited, 98 (75.96 %) participated in the study. Most were of Guarani ethnicity, single, had lower incomes, and were educated only to the elementary level. Post-vaccination, a statistically significant increase was noted in IgG concentration (24.03 % to 37.02 %). Increases were observed in B lymphocytes (11.88 to 13.92 cells/mm3), memory B cells (13.58 to 15.96 cells/mm3), NK cells (20.23 to 24.08 cells/mm3), and non-classical monocytes (9.23 to 11.34 cells/mm3), while CD8+ T cells decreased (24.41 to 21.69 cells/mm3). Adolescents with prior exposure to the virus showed increased levels of B lymphocytes and CD8+ T cells. No significant changes were observed in other cell subpopulations from exposure to the virus. Conclusion: Elevated levels of antibodies and certain cell subpopulations were observed in vaccinated adolescents, confirming the effectiveness of the BNT162b2 vaccine in maintaining humoral and cellular responses. This study is the first to describe data from indigenous minors vaccinated against COVID-19 with the BNT162b2 vaccine, highlighting the importance of vaccination efforts and the potential need for booster doses.