Background: Very few case reports have explored a potential link between ankylosing spondylitis (AS), an autoimmune disorder, and amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative condition. We aimed to investigate whether genetic liability to AS causally influences the risk of ALS, and vice versa, using a bidirectional two-sample Mendelian randomization (MR) framework. Methods: We performed a two-sample MR study to evaluate the bidirectional causal relationship between genetic liability to ankylosing spondylitis and ALS risk. We used 6 valid single nucleotide polymorphisms (SNPs) from genome-wide association study (GWAS) data (AS: 1462 cases and 164,682 controls; ALS: 27,205 cases and 110,881 controls). We used the inverse-variance weighted (IVW) approach as the primary statistical method for causal estimation, with sensitivity analyses (including MR-Egger, weighted median, weighted mode, Mendelian Randomization Pleiotropy Residual Sum and Outlier (MR-PRESSO), leave-one-out, and single SNP analysis) to assess pleiotropy and heterogeneity. Results: There was no evidence of a causal association between genetic predispositions to ankylosing spondylitis (AS) and amyotrophic lateral sclerosis (ALS) (IVW OR = 1.01; 95% CI: 0.99–1.02; p = 0.10). The results from the weighted median, weighted mode, MR-Egger, and simple mode methods were consistent and nonsignificant. In the reverse analysis, genetic liability to ALS showed no causal effect on AS (IVW OR = 0.88; 95% CI: 0.70–1.12; p = 0.33), with similar null findings across all sensitivity methods. Conclusions: Overall, our bidirectional two-sample MR analyses provided no evidence supporting a causal relationship between AS and ALS.