Background <p>Epidemiological observations suggest a potential causal relationship between osteoarthritis and depression. Alternatively, this association might arise from the simple co-occurrence of osteoarthritis and depression due to shared genetic or environmental risk factors within the population. However, the causal nature of this relationship remains uncertain. This study aims to investigate the genetic causal relationship between osteoarthritis and depression. Methods: Two-sample single nucleotide polymorphism (SNP) information was obtained from the published genome-wide association analysis (GWAS) database, selected appropriate SNP as the tool variable, conducted two-way MR analysis by inverse variance weighted method (IVW), weighted median method (WM) and MR-Egger regression, and conducted sensitivity analysis to assess the robustness of the results. Results: (1)Effect of osteoarthritis on depression: The IVW approach found that osteoarthritis increased the risk of depression (<i>OR</i> = 1.073,95%<i>CI</i>:1.026–1.122, <i>P</i> = 0.002). Effect of depression on osteoarthritis: IVW method found depression to increase the risk of osteoarthritis (<i>OR</i> = 1.115,95%<i>CI</i>:1.014–1.226, <i>P</i> = 0.025), MR-gger regression intercept test (<i>P</i> &gt; 0.05); the results of heterogeneous test showed <i>P</i>-values &gt; 0.05, no heterogeneity.(2)The results confirm that there is a causal relationship between osteoarthritis and depression, that is, osteoarthritis may be a risk factor for depression, at the same time, depression and osteoarthritis also have a causal relationship, that is, depression may be a risk factor for osteoarthritis. Conclusion: Osteoarthritis may have a bidirectional causal relationship with depression.</p>