<p>Antarctic sea-ice microorganism lives in polar sea-ice channels, in which the salinity can be three times that of seawater in winter and close to freshwater in summer. Here, we investigated the survival and adaptive strategies of Antarctic yeast <i>Rhodotorula mucilaginosa</i> AN5 treated individually with high (150‰) and low (0‰) salinity to simulate the natural environment. The results showed that salinity changes did not significantly affect the growth of yeast AN5. Scanning electron microscope (SEM) observation revealed that the cell size increased under both hyper- and hyposalinity compared to control, and more extracellular substances were observed, especially under hypersalinity stress. Biochemical factors determination indicated that after high salinity exposure, the increased antioxidant systems eliminated the induced ROS, while under low salinity stress, ROS and the antioxidant system were decreased. The proteomic analysis based on iTRAQ and PRM technology revealed that 86 proteins were up-regulated and 388 were down-regulated. Under high salinity stress, the most predominant enrichment pathway was nucleocytoplasmic transport. In addition, high salinity exposure inhibited fatty acid metabolism, the one-carbon pool by folate, and ubiquitin-mediated proteolysis. Under low salinity stress, the glyoxylate cycle pathway was induced, and aldolase was down-regulated, indicating that the energy demand in yeast survival was supplied by the catabolism of lipids. Meanwhile, low salinity also limited the synthesis of RNA, DNA, and protein by inhibiting the ribosome biogenesis and pyrimidine metabolism pathways. Generally, these results provide comprehensive insights into the molecular mechanisms underlying the adaptation of Antarctic sea-ice yeast <i>R. mucilaginosa</i> to high and low salt stress.</p>