Mainland Southeast Asia underwent dramatic changes after the mid-first millennium b.c.e., as its populations embraced new metallurgical and agricultural technologies. Southeast Asians transformed their physical and social environments further through their participation in international maritime trade networks. Early state formation characterized much of the mainland by the mid-first millennium c.e. We examined a protohistoric (200 b.c.e.–200 c.e.) skeletal sample from the Vat Komnou cemetery at Angkor Borei in the Mekong Delta (southern Cambodia) to understand the health impacts of this changing environment. Degenerative joint disease patterns indicate a distinct sexual division of labor. Although intentional dental filing was practiced, its impact on oral-dental health could not be determined. Dental pathologies suggest a mixed diet with more fibrous foods and a lower reliance on soft, processed agricultural foods. A broad-spectrum diet and varied use of the local environment are inferred from the faunal evidence. Stable isotope ratios indicate a relatively greater reliance on fish and estuarine dietary resources than on terrestrial protein. Affinities with other groups in the region are suggested by the cultural practices of the relatively tall, healthy inhabitants from Vat Komnou.