The Papua New Guinean Highlands has been continuously inhabited for 20,000 years. Since initial settlement at altitude, these populations have been exposed to low oxygen availability, which potentially resulted in stress exposure. In this project we measured phenotypes related to altitude in 70 Papuan participants living at high altitude (2300–2700 m above sea level (a.s.l).) and 86 Papuan participants living at low altitude (<100 m a.s.l.). Papuan New Guinean highlanders significantly differed in height, waist circumference, pulmonary capacity, chest depth and haemoglobin concentration. To detect if these phenotypic differences resulted from genetic selection, we looked for signatures of positive selection in 54 newly sequenced Papua New Guinean highlander genomes. We identified 21 independent genomic regions under selection. These genomic regions include genes associated with haematological traits, brain development, pregnancy success, and metabolism. Because a variant introgressed from Denisova might have aided Tibetans inhabit high altitude environments and Papuans carry a considerable introgression rate from the same archaic human, we explored the possibility of adaptative archaic introgression in the regions under selection. Finally, we defined the most likely genetic variant to drive selection in each genomic region under selection and explored which phenotypes are controlled by these variants. This study concludes that the genomes of Papua New Guinean highlanders carry unique signs of selection that allow them to live at altitude successfully.