ABSTRACT Background Psoriasis and depression frequently coexist, creating a complex, bidirectional relationship that complicates treatment. This study, integrating clinical assessments with transcriptomic and metabolomic analyses, hypothesizes that TYK2 (tyrosine kinase 2) inhibitors possess a dual therapeutic potential to simultaneously address both dermatological manifestations of psoriasis and the frequently accompanied depressive symptoms. Methods In a cohort of 298 psoriasis patients evaluated using the Hospital Anxiety and Depression Scale (HADS), participants were categorized into a TYK2 inhibitor group, a Janus kinase (JAK) inhibitor group, and a non‐JAK pool (comprising interleukin [IL]‐23 biologics, IL‐17 biologics, and other treatments) to avoid overlapping JAK pathway inhibition. Statistical analysis was conducted using generalized linear models (GENMOD), with adjustments for the following covariates: age, sex, Psoriasis Area and Severity Index (PASI), body surface area (BSA), prior systemic or biologic therapy within 12 months, disease duration, and phototherapy history. Results For HADS‐D scores, the TYK2 inhibitor group showed significantly lower values compared with the non‐JAK pool ( β = 1.23, 95% confidence interval [CI]: 0.37–2.10). However, no significant differences were observed when compared with the IL‐23 biologics group ( β = 0.67, 95% CI: −0.76–2.10) or the JAK inhibitor group ( β = 0.84, 95% CI: −1.54–3.21). Transcriptomic analysis of peripheral blood revealed significant downregulation of genes related to the IL‐6 receptor, long‐term depression pathways, and Th17 cell differentiation, while pathways associated with neuronal activity were upregulated. Metabolomic profiling highlighted a decrease in kynurenic acid, which is known for its pro‐inflammatory and depressive effects, and an increase in 1H‐indole‐3‐propanoic acid, an anti‐inflammatory metabolite with neuroprotective properties. It is important to note that these findings are based on exploratory omics analyses, for which false discovery rate (FDR) control was applied. Conclusions These findings provide a hypothesis that TYK2 inhibitors disrupt the persistent “peripheral inflammation–central depression” cycle by targeting the IL‐23/Th17 axis and modulating the IL‐6/tryptophan metabolic hub. This innovative, multi‐targeted approach represents a possibility for treating psoriasis with comorbid depression, offering not only clinical improvements in both skin and mood symptoms but also enhanced patient adherence to treatment regimens.