Chronic stress significantly contributes to the development of anxiodepression, with marked sex differences in hippocampal dysfunction. This study examines the phosphoproteomic features related to sex and phenotype in a chronic restraint stress mouse model. Female and male mice were categorized into anxiodepression-susceptible (AD-Sus) and insusceptible (Insus) groups, followed by a comparative analysis of hippocampal phosphoproteomes using 4D label-free quantitative proteomics. The findings revealed distinct phosphorylation profiles linked to sex and phenotype, with phosphoproteins primarily associated with the MAPK signaling pathway, as confirmed by subsequent kinase-substrate interaction analyses. In females, significant enrichment was observed in the thyroid hormone signaling pathway and long-term potentiation, while males exhibited notable enrichment in the serotonergic synapse pathway, suggesting differential modulation of emotional responses by serotonin. Moreover, GABAergic synapses were more prevalent in the Insus group compared to the AD-Sus group, and the cGMP-PKG signaling pathway was enriched in both male and female AD-Sus groups. MAPK1 was identified as the kinase with the highest number of phosphorylated substrates across all groups. Key phosphorylation targets included Stmn1 (S38) and Pdha1 (S232) in both female AD-Sus and Insus groups, while Stmn1 (S38) and Mapt (T523) were identified in female and male Insus groups. In contrast to the AD-Sus group, the Insus group exhibited additional kinases, aside from MAPK1, associated with a substantial number of substrates. This suggests kinase regulation mechanism in the Insus group may be more complex, whereas the regulatory role of MAPK1 is more pronounced in the AD-Sus group. Overall, this study enhances our understanding of the biological mechanisms underlying stress-induced anxiodepression and identifies potential therapeutic targets and pathways specific to sex and phenotype.