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Background: The incidence of non‐alcohol fatty liver disease (NAFLD) has been increasing annually with the improvement of living standards. Numerous epidemiological observations have linked sex hormone‐binding protein (SHBG) levels to NAFLD. However, evidence of the causal role of SHBG in the development and progression of NAFLD is still absent. Therefore, a systematic assessment of the causal relationship is needed. Method: A two‐sample Mendelian randomisation (MR) analysis was conducted. Genome‐wide association study (GWAS) data for SHBG were obtained online from the IEU database (ebi‐a‐GCST90012111) as exposure. GWAS data from the NAFLD of the Finngen consortium were used for preliminary analysis, while NAFLD data from another GWAS involving 8434 participants were used for replication and meta‐analyses. Causal effects were investigated with inverse variance weighted (IVW), weighted median and MR–Egger regression. Sensitivity analyses including Cochran's Q test, leave‐one‐out analysis and MR–Egger intercept analysis were simultaneously conducted to assess heterogeneity and pleiotropy. Results: After rigorous selection, 179 single‐nucleotide polymorphisms (SNPs) were identified as strongly correlated instrumental variables. Preliminary analysis suggested a significant causal relationship between genetically determined serum SHBG levels and NAFLD [odds ratio (OR) IVW =.54, 95% confidence interval (CI) =.30–.98, p =.043], supported by the results of the replication analysis (ORIVW =.61, 95% CI =.46–.81, p =.0006) and further meta‐analysis (OR =.59, 95% CI =.46–.77, p <.0001). Conclusion: The genetic tendency to high levels of SHBG was causally correlated with a reduced risk of NAFLD, indicating that circulating high levels of SHBG was a protective factor for NAFLD. [ABSTRACT FROM AUTHOR]