A recent study has reported that anti-reflux surgery reduced the risk of lung cancer. However, the exact causal association between gastro-esophageal reflux disease (GORD) and lung cancer remains obscure. Therefore, we conducted a multivariable and network Mendelian randomization (MR) study to explore this potential association and mediation effect.Independent single nucleotide polymorphisms (SNPs) strongly associated with GORD were selected as instrumental variables (IVs) from the corresponding genome-wide association studies (GWAS). The summary statistics were obtained from the largest GORD GWAS meta-analysis of 367 441 (78 707 cases) European individuals, and the summary statistics of lung cancer and pathological subtypes came from International Lung Cancer Consortium (ILCCO) and FinnGen databases. Univariable and multivariable MR analyses were performed to investigate and verify the causal relationship between genetically predicted GORD and lung cancer. Network MR analysis was conducted to reveal the mediating role of GORD between smoking initiation and lung cancer.The univariable MR analysis demonstrated that GORD was associated with an increased risk of total lung cancer in both ILCCO [inverse variance weighted (IVW): odds ratio (OR) = 1.37, 95% confidence interval (CI) 1.16-1.62, P = 1.70E-04] and FinnGen database (IVW: OR = 1.25, 95% confidence interval CI 1.03-1.52, P = 2.27E-02). The consistent results were observed after adjusting the potential confounders [smoking traits, body mass index (BMI) and type 2 diabetes] in multivariable MR analyses. In subtype analyses, GORD was associated with lung adenocarcinoma (IVW: OR = 1.27, 95% CI 1.02-1.59, P = 3.48E-02) and lung squamous cell carcinomas (IVW: OR = 1.50, 95% CI 1.22-1.86, P = 1.52E-04). Moreover, GORD mediated 32.43% (95% CI 14.18-49.82%) and 25.00% (95% CI 3.13-50.00%) of the smoking initiation effects on lung cancer risk in the ILCCO and FinnGen databases, respectively.This study provides credible evidence that genetically predicted GORD was significantly associated with an increased risk of total lung cancer, lung adenocarcinoma and lung squamous cell carcinomas. Furthermore, our results suggest GORD is involved in the mechanism of smoking initiation-induced lung cancer.© The Author(s) 2023; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.