The impact of artificially sweetened beverages (ASBs) consumption on obesity-related cancers (ORCs) risk remains controversial. To address this challenging issue, this study employed wide-angle mendelian randomization (MR) analyses to explore the genetic causality between ASB consumption and the risk of ORCs, thereby effectively minimizing the impact of external confounders.We conducted a suite of analyses encompassing univariable, multivariable, and two-step MR to evaluate causal associations between ASB consumption (samples = 85,852) and risk of ORCs (total samples = 2,974,770) using summary statistics from genome-wide association studies (GWAS). Total, direct, and intermediary effects were derived by performing inverse-variance weighted (IVW), MR-Egger, weighted mode, weighted median, and lasso method. Additionally, we performed an extensive range of sensitivity analyses to counteract the potential effects of confounders, heterogeneity, and pleiotropy, enhancing the robustness and reliability of the findings.Genetically predicted ASB consumption was positively associated with the risk of colorectal cancer (CRC, p = 0.011; OR: 6.879; 95% CI: 1.551, 30.512 by IVW) and breast cancer (p = 0.022; OR: 3.881; 95% CI: 2.023, 9.776 by IVW). Multivariable analysis yielded similar results. The results of the two-step MR unveiled that body mass index (BMI) assumes a pivotal role in mediating the association between ASB consumption and CRC risk (intermediary effect = 0.068, p = 0.024).No causal connection exists between ASB consumption and the majority of ORCs, in addition to CRC and breast cancer. Additionally, our findings suggest that BMI might be a potential mediator in the association between ASB consumption and CRC.Copyright © 2024 Jin, Wu, Dong, Liu and Ma.