Background <p>An association of <i>OsCUL3c</i> with salt tolerance has been found by a genome-wide association studies (GWAS) in rice. However, its functions and mechanisms remain unexplored. We aimed to examine the role of Cullin3 of E3 ubiquitin ligase in salt stress responses.</p> Results <p>Proteomic analyses were performed to compare the <i>Atcul3a</i> mutant and wild type (WT) plants under salt stress. Our results demonstrated that an Arabidopsis mutant of <i>Cullin3a</i> (<i>Atcul3a</i>), an <i>OsCUL3c</i> homolog, exhibits a more sensitive phenotype under salt stress than the WT. Differentially expressed proteins (DEPs) that were non-salt-responsive demonstrated an overrepresentation of Gene Ontology (GO) terms associated with photosynthesis. Conversely, salt-responsive DEPs exhibited enriched GO terms linked to responses to toxic substances and involvement in glutathione metabolism. The role of <i>OsCUL3c</i> in salt tolerance was further supported by its heterologous expression in Arabidopsis. We cloned the rice <i>OsCUL3c</i> gene and expressed it in Arabidopsis, both in WT and <i>Atcul3a</i> mutant backgrounds. Complementation and over-expression lines featuring <i>OsCUL3c</i> expression displayed a higher germination rate, enhanced growth, and elevated photosynthetic pigment content under salt stress compared to the mutant line. Over-representation analysis on the combined proteomic datasets revealed major processes affected by the <i>Cullin3</i> mutation and overexpression, which included glutathione metabolism, carbon metabolism, photosynthesis, and translation. Upregulation of several key genes in glutathione metabolism and carbon metabolism; and downregulation of specific photosynthetic and ribosomal proteins indicate a shift toward enhanced oxidative defense and metabolic reprogramming under salt stress conditions.</p> Conclusions <p>These findings highlight <i>Cullin3</i> as a key salt tolerance regulator by coordinating multiple pathways.</p>