Global shift in salinity regimes along with the expansion of hypoxic zones in aquatic systems may pose serious threats even to euryhaline fish. The functional attributes of gill to hypoxia stress and salinity challenge relation to the ion transporters and water channels have not yet delineated in euryhaline fish. We therefore, explored the pattern of ion transporter proteins abundance and expression of hypoxia inducible factor 1α (HIF1 α) and aquaporin 1 (AQP 1) in pearl spot (Etroplus suratensis) exposed to acute hypoxia stress and salinity challenge. Salinity challenge influenced HIF1 α expression and heat shock protein (HSP 70) abundance under hypoxia stress. The increase in Na+/K+-ATPase (NKA) activity and abundance went almost hand in hand with the Na+/K+-2Cl- cotransporter (NKCC) protein abundance in response to salinity increase. On the contrary, hypoxia stress demanded inhibition of both the NKA and NKCC in gill irrespective of salinity. The mRNA expression of AQP1 was deficient in gill regardless of the salinity change, whereas, hypoxia up-regulated mRNA expression of AQP1 depending on salinity level. The evidence is thus presented for the first time that, ion transporters such as NKA and NKCC along with AQP1 act as functional gill markers which respond differentially to hypoxia stress and salinity challenges or both. The results further provide evidence for an inverse expression pattern of ion transporters and water channel protein in gill as a result of the osmorespiratory compensatory response of the euryhaline fish during hypoxia stress-salinity interaction.