Abstract : Lichen simplex chronicus (LSC) is a chronic pruritic dermatosis characterized by a persistent itch–scratch cycle that significantly impairs patients’ quality of life. The pathogenesis of LSC involves complex interactions among neuroimmune mechanisms, psychological stress, and dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis. Emerging evidence indicates that the gut microbiota plays a role in modulating stress responses and inflammation through the gut–brain–skin axis. Lactobacillus plantarum has been reported to exert immunomodulatory and anti-stress effects; however, its impact on neuroimmune biomarkers and clinical severity of LSC remains limitedly explored. To evaluate whether adjunctive Lactobacillus plantarum PS128 administered for four weeks improves pruritus severity and dermatology-specific quality of life in patients with lichen simplex chronicus, and to explore its effects on serum cortisol (stress-related biomarker) and selected inflammatory biomarkers (IL-31, TNF-α, and eosinophil counts). This experimental analytic study employed an intervention and control group design involving patients with LSC. Participants received either Lactobacillus plantarum PS128 supplementation or control for four weeks. Outcome measures included serum cortisol, IL-31, TNF-α, peripheral blood eosinophil counts, pruritus severity assessed using the Visual Analogue Scale (VAS), stress-related quality of life assessed using the Dermatology Life Quality Index (DLQI), and clinical severity evaluated using the Objective Clinical Severity Score–LSC (OCSS-LSC). A strong, statistically significant positive correlation was observed between changes in serum cortisol levels and changes in OCSS-LSC scores (rₛ = 0.629; p < 0.001). In contrast, changes in interleukin-31 (rₛ = −0.268; p = 0.095), TNF-α (rₛ = −0.135; p = 0.406), and eosinophil counts (rₛ = 0.160; p = 0.323) were not significantly correlated with changes in OCSS-LSC scores. Four-week supplementation with Lactobacillus plantarum PS128 effectively reduced pruritus severity in patients with LSC, potentially mediated through modulation of stress responses and non-eosinophilic neuroimmune pathways. However, this intervention did not result in significant changes in systemic inflammatory biomarkers IL-31, TNF-α, or eosinophil counts after adjustment for baseline values. These findings indicate that clinical improvement in LSC may occur independently of significant changes in systemic inflammatory biomarkers and highlight the need for longer intervention durations to comprehensively evaluate the immunological effects of probiotic supplementation.