INTRODUCTION: Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy, yet its pathophysiology remains unclear. Inflammation, fibrosis, and metabolic factors have been implicated in animal models, but evidence from human studies is inconsistent. OBJECTIVES: To comprehensively characterize blood-based biomarker alterations in CTS compared with healthy controls. A secondary aim was to summarize reported associations between biomarkers and clinical outcomes. METHODS: Seven databases were searched from inception to February 2026. Two reviewers independently screened the included studies, extracted data and assessed methodological quality using the Newcastle-Ottawa Scale. Meta-analyses were performed when at least two comparable studies were available with a multilevel random-effects approach for the main meta-analyses, and random-effects or fixed-effects for subgroups meta-analyses. Sensitivity analyses were performed through "leave-one-out" method and certainty of evidence was evaluated through GRADE approach. RESULTS: Meta-analyses showed significantly higher blood levels of fibrosis-related markers [SMD (95% CI) = 1.64 (0.96/2.33)], anti-inflammatory markers [SMD (95% CI) = 1 (0.1/1.89)], proinflammatory markers [SMD (95% CI) = 0.63 (0.13/1.12)], and lower levels of vitamins and minerals [SMD (95% CI) = -0.75 (-1.49/-0.005)]. At individual level, increased concentrations of CCL4, CXCL10, CCL2, CXCL8, CRP, IL4, neutrophils, VEGF, and MDA were observed, along with decreased vitamin D levels. CONCLUSION: CTS might be associated with systemic alterations in inflammatory and fibrotic pathways, and reduced vitamin D levels. Despite low certainty of evidence, high heterogeneity and the inability to confer causality from observational data, these biomarkers may inform future prospective research.