To provide initial data on local SARS-CoV-2 epidemiology and spread in indigenous communities in north-eastern Colombia, respiratory swabs and serum samples from volunteers of indigenous communities were examined in March and April 2021. Samples from non-indigenous Colombians from the same villages were included as well. While previous exposure to SARS-CoV-2 was assessed by analysing serum samples for IgG and IgM with a rapid antibody point-of-care-test (POCT), screening for active infections was carried out with an antigen POCT test and real-time PCR from nasal swabs. In 380 indigenous and 72 non-indigenous volunteers, 61 (13.5%) active infections and an additional 113 (25%) previous infections were identified using diagnostic serology and molecular assays. Previous infections were more frequent in non-indigenous volunteers, and relevant associations of clinical features with active or previous SARS-CoV-2 infections were not observed. Symptoms reported were mild to moderate. SARS-CoV-2 was frequent in the assessed Colombian indigenous communities, as 38.5% of the study participants showed signs of exposure to SARS-CoV-2, which confirms the need to include these indigenous communities in screening and vaccination programs.