This study evaluates DNA damage and multi-element exposure in populations from La Mojana, a region of North Colombia heavily impacted by artisanal and small-scale gold mining (ASGM). DNA damage markers from the cytokinesis-block micronucleus cytome (CBMN-Cyt) assay, including micronucleated binucleated cells (MNBN), nuclear buds (NBUDs) and nucleoplasmic bridges (NPB), were assessed in 71 exposed individuals and 37 unexposed participants. Exposed individuals had significantly higher MNBN frequencies (PR = 1.26, 95% CI: 1.02-1.57, p = 0.039). Principal Component Analysis (PCA) identified the Soil-Derived Mining-Associated Elements (PC1), including V, Fe, Al, Co, Ba, Se and Mn, as being strongly associated with high MNBN frequencies in the exposed population (PR = 10.45, 95% CI: 9.75-12.18, p < 0.001). GAMLSS modeling revealed non-linear effects of PC1, with greater increases in MNBN at higher concentrations, especially in exposed individuals. These results highlight the dual role of essential and toxic elements, with low concentrations being potentially protective but higher concentrations increasing genotoxicity. Women consistently exhibited higher MNBN frequencies than men, suggesting sex-specific susceptibilities. This study highlights the compounded risks of chronic metal exposure in mining-impacted regions and underscores the urgent need for targeted interventions to mitigate genotoxic risks in vulnerable populations.