Background C-X-C Motif Chemokine Receptor (CXCR4) is an oncogene that widely studied and associated with worse clinicopathological features and prognosis outcome on many types of cancer. Beside that, significance of CXCR4 expression on clinicopathological features and prognostic on osteosarcoma (OS) require further validation. Aim We conducted a meta-analysis to evaluate association between positive CXCR4 expression with clinicopathological features, and prognosis in OS. Methods Literature searches on Pubmed, Cochrane Library and Web of Science was conducted systematically up to December 2021 to find relevant references. Effect of CXCR4 expression on clinicopathological characteristic and prognostic were analyzed using Review Manager 5.4 (Cochrane Collaboration, Oxford, UK). Significance value less than 0.05 was considered statistically significant. Results By considering inclusion and exclusion criteria, 940 patients from 12 studies were suitable to included in qualitative analysis, and 10 studies were suitable for quantitative analysis. Association between CXCR4 expression and OS clinicopathological features was found significant on metastasis (OR = 4.01, 95%CI = 1.58–10.18; p = 0.003), stage (stage III & IV vs I & II, OR = 6.52, 95%CI = 1.05–40.62; p = 0.04), and tumor primary site (femur/tibia vs other, OR = 1.60, 95%CI = 1.04–2.45; p = 0.03), but not associated with histological type, gender, and age. Furthermore, CXCR4 expression is associated with poor overall survival in OS (HR = 2.13, 95%CI = 1.78–2.55; p < 0.001). Conclusion In conclusion, the results of our meta-analysis suggest that CXCR4 expression may be valuable as a histopathological predictor of poor clinicopathological features and prognosis of OS.