Background <p>The kynurenine pathway (KP) represents a primary route of tryptophan (TRP) catabolism and is critically regulated by pro-inflammatory cytokines through induction of indoleamine 2,3-dioxygenase (IDO). The kynurenine-to-tryptophan (KYN/TRP) ratio serves as an indirect measure of IDO activity and is increasingly recognized as a biomarker of peripheral neuroinflammatory activation in psychiatric disorders. However, the directionality and clinical significance of KYN/TRP dysregulation specifically in first-episode drug-naive psychosis (FEP) remain incompletely characterized, representing a critical gap in our understanding of early psychosis pathophysiology. This systematic review and meta-analysis synthesized available evidence on peripheral KYN/TRP ratios in individuals with drug-naive FEP compared to healthy controls (HC), and examined sources of heterogeneity including biospecimen matrix, analytical platform, and clinical covariates.</p> Methods <p>A comprehensive literature search was conducted in PubMed, Scopus, and Web of Science from inception to May 2026. Studies reporting peripheral KYN and/or TRP concentrations in FEP patients with sufficient data for effect size computation were included. Study quality was assessed with the Newcastle-Ottawa Scale. Pooled SMDs were estimated using random-effects inverse-variance methods where complete study-level data were available. Heterogeneity was evaluated using Cochran Q, I-squared, and prediction intervals where estimable. Subgroup summaries were performed for medication status, biospecimen matrix, assay platform, and study quality. Meta-regression was not performed because the primary drug-naive pool contained only five studies, below the pre-specified k ≥ 10 threshold. Publication bias was assessed visually using funnel plots; Egger regression was not used as a confirmatory test given the small number of studies.</p> Results <p>Fourteen studies encompassing 1,127 participants (563 FEP patients, 564 HC) met inclusion criteria. Five studies comprised the primary drug-naive pool. Meta-analysis of the primary pool yielded a non-significant pooled SMD of + 0.42 (95% CI: -0.08 to + 0.92; I-squared = 78%), indicating substantial heterogeneity and a directional but inconclusive trend toward KYN/TRP elevation. Sensitivity analysis restricted to medicated or mixed-treated FEP yielded a significant SMD of + 0.55 (95% CI: +0.12 to + 0.97). IDO protein-level studies consistently demonstrated significant elevation. Subgroup analyses stratified by medication status, biospecimen matrix, and assay platform were performed descriptively; meta-regression was not performed given the small primary evidence base. Risk of bias was generally low-to-moderate (NOS: range 5 to 9 stars).</p> Conclusions <p>The peripheral KYN/TRP ratio in FEP shows a directional trend toward elevation, consistent with IDO-mediated neuroinflammatory activation, but findings remain heterogeneous across studies. The KYN/TRP ratio should currently be considered a hypothesis-generating candidate biomarker of neuroinflammatory activation in early psychosis that requires further validation in prospective, adequately powered studies before clinical translation can be established. Standardization of analytical methods and prospective designs with matched controls are urgently needed to resolve observed inconsistencies.</p>