Background: Latin America and the Caribbean (LAC) has presented some of the highest numbers of cases and deaths due to COVID-19 in the world. Even though indigenous communities represent 8% of the total population in this region, the impact of COVID-19 on this historically vulnerable population has only been briefly explored. Thus, this study aimed to estimate the seroprevalence and lethality attributable to SARS-CoV-2 in the indigenous population of LAC. Methods: A systematic review was conducted utilizing multiple databases (registry PROSPERO: CRD42020207862). Studies published in English, Spanish or Portuguese were selected between December 1st, 2019, and April 14th, 2021. The evaluation of the quality of the study was carried out utilizing the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. A qualitative synthesis of the data analyzed was conducted following the MOOSE and PRISMA declarations. Results: Fifteen studies met the inclusion criteria. Eleven studies were carried out in a Brazilian population, three in a Mexican population, and one in a Colombian population. Four studies reported data about the seroprevalence of SARS-CoV-2 in indigenous populations of Brazil (range: 4.2-81.65%). Twelve studies reported lethality in indigenous people (eight in Brazil, three in Mexico, and one in Colombia). In Brazil, a lethality of 53.30% was described in a hospital setting and between 1.83% and 4.03% in community studies. In Mexico, the lethality of COVID-19 ranged between 16.5% and 19.9%. Meanwhile, in Colombia, a lethality of 3.41% was reported. Most studies were deemed to be of good quality. Conclusions: Despite COVID-19 affecting indigenous populations of LAC, there is limited evidence of the seroprevalence and lethality of the infection by SARS-CoV-2 in this population. Future investigations should ensure standardized methods that allow comparability among studies and ensure the precision of the results obtained.