Background: Preliminary epidemiological studies have postulated that the herpes virus may substantially contribute to the etiology and progression of various forms of arthritis. However, the causal relationship between herpes virus infection and Osteoarthritis (OA) remains ambiguous. This two-sample Mendelian randomization (MR) study endeavors to comprehensively examine the impact of genetically predicted Epstein-Barr Virus (EBV), herpes simplex virus (HSV), and Varicella-Zoster Virus (VZV) on OA susceptibility. Methods: Summary data for EBV, HSV, and VZV were acquired from the FinnGen biobank. Genome-Wide Association Study summary statistics for OA encompassing knee, hip, knee/hip, and any OA were compiled through a meta-analysis . The primary MR analysis method employed was the Inverse-Variance Weighted (IVW). Additionally, we conducted secondary analyses utilizing the weighted-median, Maximum Likelihood method, MR-Egger regression, and the MR pleiotropy residual sum and outlier test to ensure the robustness of our findings. Results: After Bonferroni correction, genetically predicted VZV infection was significant associated with a higher risk of knee OA (odds ratio [OR] = 1.07, 95% confidence interval [CI]: 1.03-1.12; PIVW = 0.002 using the IVW method). We also noticed VZV infection was suggestively associated with a higher risk of knee/hip OA (OR = 1.04, 95% CI: 1.00-1.08, PIVW = 0.030), and any OA (OR = 1.03, 95% CI: 1.00-1.06, PIVW = 0.020). The MR-Egger and weighted median methods yielded congruent results. Nevertheless, our analysis did not reveal any causal association between genetically predicted EBV and HSV infections and OA. In the reverse MR study, statistically significant associations between OA and the three herpesvirus infections were not observed. Conclusion: The study demonstrated a causal relationship between VZV infection and the risk of OA, particularly knee OA. Future endeavors should prioritize investigating the potential underlying mechanisms to further elucidate this associatio