This systematic review and meta-analysis aimed to assess the effectiveness of chemical prophylaxis in preventing venous thromboembolism (VTE) and spinal epidural hematoma (SEH) following degenerative spine surgery. The effectiveness of chemical prophylaxis in preventing VTE and SEH following degenerative spine surgery remains controversial, with variability in protocols and a lack of comprehensive, high-quality studies guiding optimal prophylaxis strategies. An electronic search across five databases, including Medline, Embase, Cochrane Library, Scopus, and Web of Science, was performed on February 2, 2024 to identify studies comparing chemical with nonchemical prophylaxis for VTE among degenerative spine surgery patients. Studies reporting on VTE (deep vein thrombosis and pulmonary embolism) and SEH were included. Patients under 18 years of age and those with trauma, tumors, infections, congenital deformities, and adolescent idiopathic scoliosis were excluded. Data on study characteristics, clinical details, and outcomes were collected. Metaanalyses were conducted to compare patients received chemical and non-chemical prophylaxis for VTE. Subgroup analyses according to the type of medication used for the chemical prophylaxis, study design, dosage regimen, and study quality were also performed. A total of 17 studies involving 5,383 patients satisfied our eligibility criteria. No significant difference in VTE incidence was observed between patients receiving chemical and non-chemical prophylaxis (risk ratio, 1.09; 95% confidence interval, 0.82 to 1.46; p=0.988). Subgroup analyses also showed consistent results (p>0.05). SEH incidence was reported in five studies (29.4%) involving five cases, among whom three and two were in the control and chemoprophylaxis groups, respectively. Perioperative chemoprophylaxis may not significantly alter VTE or SEH rates following degenerative spine surgery. This study highlights the need for further high-quality studies to establish better recommendations for VTE prophylaxis after degenerative spine surgeries (PROSPERO registration no., CRD42024585493).