Whole genome scans for natural selection signatures across Mexican Indigenous (MI) Populations remain underrepresented in the literature. Here, we conducted the first comparative analysis of genetic adaptation in MI populations using whole genome sequencing (WGS) data from 76 individuals representing 27 different ethnic groups in Mexico. We divided the cohort into Northern, Central, and Southern populations and identified signals of natural selection within and across populations. We find evidence of adaptation to pathogenic environments in all our populations, including significant signatures in the Duffy blood group gene in Central MI populations. Despite each region exhibiting unique local adaptation profiles, selection signatures on ARHGAP15, VGLL4, LINGO2, SYNDIG1, and TFAP2B were common to all populations. Our results also suggest that selection signatures falling within enhancers or promoters are usually connected to non-coding features, with notable exceptions like ARHGAP15 and GTDC1. This paper provides new evidence on the selection landscape of Mexican Indigenous Populations and lays the foundation for additional work on Mexican phenotypic characterization.