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Background/Objectives: Spinal tuberculosis (STB) is frequently misdiagnosed due to the multitude of symptoms it presents with. This review aimed to investigate the biomarkers that have the potential to accurately diagnose spinal TB in its early stages. Methods: A systematic search was conducted across multiple databases, yielding a diverse range of biomarkers categorized into complete blood count parameters, host inflammatory responses, bacterial antigens, and RNA-based markers. This review included studies on spinal tuberculosis patients, including blood serum biomarkers, while exclusion criteria included pediatric cases, cerebrospinal fluid or imaging biomarkers, co-infection with other bacteria, viruses, comorbidities, tumors, immune diseases, HIV infection, metabolic disorders, animal studies, opinion papers, and biomarkers relevant to health problems outside the disease. QUADAS-2 was used as a quality assessment tool for this review. This review identifies several promising biomarkers with significant diagnostic potential. Results: The neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), IFN-γ, CXCR3, CXCL9, CXCL10, PSMB9, STAT1, TAP1, and specific miRNA combinations demonstrated noteworthy diagnostic accuracy in distinguishing STB from other spinal pathologies. Additionally, these biomarkers offer insights into disease severity and progression. The review also highlighted the importance of combining multiple biomarkers to enhance diagnostic precision. This comprehensive systematic review underscores the potential of biomarkers to revolutionize the diagnosis of spinal tuberculosis. By integrating these markers into clinical practice, healthcare providers can achieve earlier and more accurate diagnosis, leading to improved patient care and outcomes. Conclusions: The combination of multiple biomarkers, including NLR, PSMB9, STAT1, and specific miRNAs, demonstrates promising diagnostic accuracy. [ABSTRACT FROM AUTHOR]