This study aimed to estimate the COVID-19 lethality in the Mexican Indigenous population from 2020 to 2022, considering clinical characteristics and social conditions. Data were retrieved from the Epidemiological Surveillance System of Respiratory Diseases, identifying the COVID-19-positive cases among the Indigenous population. Lethality was evaluated per clinical conditions and vulnerability due to social deprivation. The number of COVID-19-positive cases in the Indigenous population represented 0.7% of the total number of cases. The case fatality rate in the Indigenous population was 9.8% against 4.6% in the non-Indigenous population. Lethality was higher in men. However, the association with diabetes, hypertension, chronic kidney disease, obesity, and smoking was lower in the Indigenous population than in the non-Indigenous population. A greater vulnerability to social conditions was identified among the Indigenous population than the non-Indigenous population, mainly regarding income, education, and access to health services.