Short-term phenotypic plasticity and long-term genetic adaptation are two key evolutionary processes that mediate organismal persistence in a new environment. But generally, there are few vertebrate systems where the molecular architecture of such plastic and genetic changes has been simultaneously characterized. Birds residing across elevational gradients are known to thrive in rapid and long-term environmental stimuli, demonstrate quantifiable plastic and adaptive traits, and thus can be a suitable model system to study molecular mechanisms of phenotypic plasticity and genetic adaptation. Here, we studied three species from the genus Perdix (Phasianidae, Galliformes): Tibetan Partridge (Perdix hodgsoniae), Daurian Partridge (Perdix dauurica), and Grey Partridge (Perdix perdix) by using an integrative approach of population and comparative genomics, transcriptomics, and field-based transplantation experiments. We identified a 60-kilobase haplotype encompassing the ESR1 gene, a ligand-activated transcription factor, showing strong genetic divergence between populations of Tibetan partridges adapted to different altitudes. We identified six SNPs in the ESR1 gene fixed for derived alleles in high-altitude populations that are strongly conserved across vertebrates, which are likely key genetic changes associated with high-altitude adaptation in Tibetan partridge. We also identified strong genetic divergence in additional genes associated with the regulation of apoptosis pathways, possibly indicating genetic adaptation to long-term chronic hypoxia in a high-altitude environment. Transcriptome analysis identified regulation of apoptosis, glycolysis, and response to hypoxia as key pathways among differentially expressed genes between populations of Tibetan partridges residing across the elevational gradient. Similarly, transcriptome analysis in birds transplanted from high to low elevation have identified differential expressed genes related to the immune system, and to stress response (mainly heat). Comparative transcriptomics analyses among Tibetan partridges in their “native” and “transplanted” habitats indicated that there are different suites of genes responding to short-term physiological acclimation or long-term adaptation in this species. However, we found two genes associated with the HIF-1 signaling pathway; Lactate Dehydrogenase-A (LDHA) and Aldolase C (ALDOC) were differentially expressed both (a) across the native populations along the elevational gradient and (b) after experimental transplantation from high to low elevation. Our results highlight Tibetan partridges as a useful study system to explore the genetic architecture associated with short-term acclimation and long-term genetic adaptation to high altitudes.