ObjectiveTo determine whether adiponectin levels and the risk of trigeminal neuralgia (TN) were causally related, a two-sample Mendelian Randomization (MR) study design was used. MethodsWe obtained data regarding adiponectin from the UK Biobank genome wide association studies (GWAS) (n = 39,883) as the exposure and TN, using GWAS summary statistics generated from FinnGen, (total n = 195 847 159; case = 800, control = 195 047) as the outcome. We conducted a two-sample Mendelian randomization analysis employing inverse variance-weighted (IVW), MR-Egger regression, weighted median, and weighted mode analyses. ResultsWe selected 14 single nucleotide polymorphisms (SNPs) with genome-wide significance from the GWAS on adiponectin as instrumental variables. Based on the IVW method, a causal association between adiponectin levels and TN was evidenced (OR= 0.577, 95 %CI: 0.393–0.847). MR‐Egger regression revealed that directional pleiotropy was unlikely to be biasing the result (intercept = –0.01; P = 0.663), but it showed no causal association between adiponectin and TN (OR=0.627, 95 %CI: 0.369–1.067). However, the weighted median (OR=0.569, 95 %CI: 0.353–0.917) and Weighted mode (OR= 0.586, 95 %CI: 0.376–0.916) approach yielded evidence of a causal association between adiponectin and TN. Cochran's Q-statistics and funnel plots indicated no evidence of heterogeneity or asymmetry, indicating no directional pleiotropy. ConclusionThe results of the MR analysis suggested that adiponectin may be causally associated with an increased TN risk.