Mexico faced a significant burden from the COVID-19 pandemic. Since the pandemic’s onset in 2020, numerous studies have underscored the substantial risk of COVID-19 death among Indigenous individuals. This study aims to assess COVID-19 vaccine uptake among Indigenous language speakers in Mexico, focusing on understanding the barriers they face in obtaining access to vaccines. We used Encuesta Nacional de Salud y Nutrición Continua (ENSANUT) 2022, a nationally representative health survey in Mexico to analyze data on self-reported COVID-19 vaccine status, reasons for not getting vaccinated, and other relevant covariates. We employed logistic regression to estimate odds ratios (ORs) for vaccine uptake and uptake barriers, all models were adjusted for potential confounders. Among 34,051 participants, 1793 individuals (5.23%) reported speaking an Indigenous language. Indigenous language speakers were found to have a lower vaccination rate (63%) compared to non-Indigenous language speakers (81%) (p <0.005). They were also 59% less likely to be vaccinated against COVID-19 (OR 0.41, 95% CI 0.27–0.62), even when adjusted for confounders. Among unvaccinated individuals, Indigenous language speakers were more likely to cite negative beliefs about the vaccine or fear as reasons for not being vaccinated (OR 1.82, 95% CI 1.11–3.00) while being less likely to report access barriers (OR 0.62, CI 95% 0.42–0.91). This study highlights disparities in COVID-19 vaccine uptake among Indigenous language speakers in Mexico. The findings underscore the urgent need for targeted, culturally appropriate public health interventions and the consideration of social and ethnic vulnerability in prioritizing vaccinations.