BackgroudPlasma lipids and alcohol intake frequency have been reported to be associated with the risk of osteoarthritis (OA). However, it remains inconclusive whether plasma lipids and alcohol intake frequency play a role in the development of OA.MethodsThe study employed a comprehensive genome-wide association database to identify independent genetic loci strongly linked to plasma lipids and alcohol intake frequency, which were used as instrumental variables. The causal association between plasma lipids, alcohol intake frequency, and the risk of OA was then analyzed using two-sample Mendelian randomization methods such as inverse variance weighted (IVW), MR-Egger regression, and weighted median estimator (WME), with odds ratios (ORs) as the evaluation criteria.ResultsA total of 392 SNPs were included as instrumental variables in this study, including 32 for total cholesterol (TC), 39 for triglycerides (TG), 170 for high-density lipoproteins (HDL), 60 for low-density lipoproteins (LDL), and 91 for alcohol intake frequency. Using the above two-sample Mendelian Randomization method to derive the causal association between exposure and outcome, with the IVW method as the primary analysis method and other MR analysis methods complementing IVW. The results of this study showed that four exposure factors were causally associated with the risk of OA. TC obtained a statistically significant result for IVW (OR = 1.207, 95% CI: 1.018–1.431,P= 0.031); TG obtained a statistically significant result for Simple mode (OR = 1.855, 95% CI: 1.107–3.109,P= 0.024); LDL obtained three statistically significant results for IVW, WME and Weighted mode (IVW: OR = 1.363, 95% CI: 1.043–1.781,P= 0.023; WME: OR = 1.583, 95% CI: 1.088–2.303,P= 0.016; Weighted mode: OR = 1.521, 95% CI: 1.062–2.178,P= 0.026). Three statistically significant results were obtained for alcohol intake frequency with IVW, WME and Weighted mode (IVW: OR = 1.326, 95% CI: 1.047–1.678,P= 0.019; WME: OR = 1.477, 95% CI: 1.059–2.061,P= 0.022; Weighted mode: OR = 1.641, 95% CI: 1.060–2.541,P= 0.029). TC, TG, LDL, and alcohol intake frequency were all considered as risk factors for OA. The Cochran Q test for the IVW and MR-Egger methods indicated intergenic heterogeneity in the SNPs contained in TG, HDL, LDL, and alcohol intake frequency, and the test for pleiotropy indicated a weak likelihood of pleiotropy in all causal analyses.ConclusionsThe results of two-sample Mendelian randomization analysis showed that TC, TG, LDL, and alcohol intake frequency were risk factors for OA, and the risk of OA increased with their rise.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12889-023-16250-1.