Introduction: Psoriasis is a chronic inflammatory skin disease frequently associated with systemic inflammation. Recently, blood cell-derived markers such as the Systemic Immune Inflammation Index (SII) and Systemic Inflammation Response Index (SIRI) have been proposed as potential biomarkers for disease activity and treatment monitoring. However, their clinical relevance in patients undergoing biological therapy, particularly IL-23 inhibitors, has not been fully explored. Objectives: To evaluate the utility of SII and SIRI in monitoring disease activity in patients with severe psoriasis treated with guselkumab, risankizumab, or tildrakizumab. Methods: This retrospective observational study included 120 patients with moderate-to-severe psoriasis treated with IL-23 inhibitors over 12 months. SII, SIRI, and Psoriasis Area and Severity Index (PASI) were assessed at baseline, six months, and 12 months. Correlations between inflammatory indices and some comorbidities were analyzed. Results: Despite significant PASI improvement across all treatment groups, SII and SIRI values showed inconsistent fluctuations and did not parallel clinical response. While SII decreased slightly in the tildrakizumab group, no consistent trend was observed in guselkumab and risankizumab cohorts. SIRI demonstrated similarly variable behavior. Weak-to-moderate correlations were noted between inflammatory indices and comorbidities such as obesity, diabetes mellitus, and hypertension. Conclusions: SII and SIRI do not reliably reflect treatment response in psoriasis patients receiving IL-23 inhibitors. Their variability and correlation with comorbidities suggest limited value as psoriasis-specific biomarkers. More targeted indicators are needed for accurate monitoring of systemic inflammation in this setting.