Acute hyperosmotic stress rapidly dehydrates cells, causing shrinkage and increasing molecular crowding, which impacts proteostasis, transcription, and translation. In response, stress-responsive MAPKs activate, modulating gene expression and translation to promote cellular adaptation. We previously reported that the ubiquitin-proteasome system (UPS) facilitates cell survival by efficiently degrading abnormal proteins generated by hyperosmotic stress through liquid-liquid phase separation. Here, we uncovered a novel hyperosmotic stress response pathway regulated by proteasomal degradation. Deep proteomic analysis revealed extensive proteome remodeling under hyperosmotic stress (approximately 150 proteins downregulated, 22 upregulated). Intriguingly, we identified a linker histone H1.2 as a substrate rapidly and specifically degraded during this stress. H1.2 is extensively ubiquitylated upon hyperosmotic stimulation, modified with complex heterotypic ubiquitin chains (K11, K29, K48 linkages). A fraction of H1.2 localized to proteasome droplets and underwent rapid, p97-dependent proteasomal degradation. We then identified the CRL4-DCAF X E3 ubiquitin ligase complex as promoting H1.2 ubiquitylation. Notably, DCAF X knockdown, which inhibited H1.2 degradation, suppressed the expression of over 200 stress-responsive genes and significantly increased cellular vulnerability to hyperosmotic stress. These findings suggest that hyperosmotic stress-dependent degradation of histone H1.2 plays a crucial role in the cellular stress response by inducing stress-responsive genes, providing a deeper understanding of how cells adapt to and survive osmotic challenges.