Steeper and sometimes extreme salinity gradients increasingly affect aquatic organisms because of climate change. Hypersalinity habitats demand powerful physiological adaptive strategies. Few teleost species have the capacity to spend their whole life cycle in salinities way over seawater levels. Focusing on the multifunctional gill, we unraveled the tilapia S. melanotheron key strategies to cope with different environmental conditions, ranging from freshwater up to hypersaline habitats. De novo transcriptome assembly based on RNAseq allowed for the analysis of 40,967 annotated transcripts among samples collected in three wild populations at 0, 40 and 80 ‰. A trend analysis of the expression patterns revealed responses across the salinity gradient with different gene pathways involved. Genes linked to ion transport, pH regulation and cell surface receptor signaling were mainly upregulated in the high salinity habitat. We identified tight junction proteins that were critical in high salinity habitats and that were different from the well-known tightening junctional proteins identified and expressed in fresh water. Expression profiles also suggest a change in the vascular tone that could be linked to an osmorespiratory compromise not only in fresh water, but also in high salinity environments. A striking downregulation of genes linked to the immune system and to the heat shock response was observed suggesting an energetic trade-off between immunity and acclimation/adaptation in the hypersaline habitat. The high expression of transcripts coding for immune and heat shock response in the freshwater habitat suggests the establishment of powerful mechanisms to protect gills from environmental threats and to maintain protein integrity. Non-directional expression trends were also detected with an upregulation of genes only in the hypersaline habitat (80 ‰) or only in the marine habitat (40 ‰). Unravel physiological strategies in S. melanotheron populations will help to better understand the molecular basis of fish euryhalinity in salinity-contrasted environments.