During periods of reduced O2 supply, the most profound changes in gene expression are mediated by hypoxia-inducible factor (HIF) transcription factors that play a key role in cellular responses to low-O2 tension. Using target-enrichment sequencing, we tested whether variation in 26 genes in the HIF signaling pathway was associated with high altitude and therefore corresponding O2 availability in three duck species that colonized the Andes from ancestral low-altitude habitats in South America. We found strong support for convergent evolution in the case of two of the three duck species with the same genes (EGLN1, EPAS1), and even the same exons (exon 12, EPAS1), exhibiting extreme outliers with a high probability of directional selection in the high-altitude populations. These results mirror patterns of adaptation seen in human populations, which showed mutations in EPAS1, and transcriptional regulation differences in EGLN1, causing changes in downstream target transactivation, associated with a blunted hypoxic response.