ObjectiveTo evaluate the genetic diversity, admixture, genetic relationships, and sex‐biased demographic processes in Mexican Mestizo (admixed) populations based on 10 X‐chromosome STRs (X‐STRs).MethodsWe analyzed the X‐STRs Decaplex system in 104 Mexican Native Americans to obtain the ancestral reference needed to complete the demographic analyses above mentioned. We included reported Iberian and Latin American (admixed) populations from Central and South America, as well as datasets from Mexican Mestizos based on Y‐linked STRs (Y‐STRs), autosomal STRs (A‐STRs), and mtDNA.ResultsHigher X‐linked Native American ancestry was observed among Latin American populations regarding that reported from A‐STRs and Y‐STRs. The interpopulation differentiation based on ancestry among Mexican Mestizos diminished according to the inheritance pattern: Y‐STRs (highest), A‐STRs, X‐STRs, and mtDNA (lowest). This finding is related to the peculiar admixture process that occurred during and after the Spanish Conquest of Mexico (and most of Latin America), involving a large number of Spanish men (Y‐chromosomes) with a lesser proportion of X‐chromosomes than autosomes; besides to the limited number of Spanish women (XX) arrived in the Americas in subsequent and shorter periods. Population expansion was detected in Mexican Mestizos from all the country, except those from the southeast region characterized by elevated indigenous ancestry, marginalization, and poorness.ConclusionsPopulation growth was detected in most Mexican Mestizos, besides more homogeneous and larger Native American ancestry based on X‐linked inheritance than that based on autosomal STRs and Y‐STRs.