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Ischemic stroke (IS) exhibits notable sex-related differences, indicating a potentially important role for sex hormones such as sex hormone-binding globulin (SHBG), estradiol, and testosterone. This study employed 2-sample Mendelian randomization (MR) to investigate the causal relationships between these sex hormones and the risk of IS and its subtypes. Genetic instrumental variables for SHBG, estradiol, and testosterone were obtained from the IEU OpenGWAS database. These instruments were analyzed to assess their causal effects on IS and its subtypes using MR methods. Sensitivity analyses were performed using several complementary MR approaches. SHBG was inversely associated with the risk of IS (OR = 0.92; 95% CI = 0.87-0.97; P = .007) and with the small-artery occlusion subtype (OR = 0.84; 95% CI = 0.75-0.94; P = .002), whereas no associations were observed for the large-artery atherosclerosis or cardioembolism subtypes. No causal effects of estradiol or testosterone on IS were identified. Our findings suggest that higher SHBG levels may reduce the risk of IS and could represent a potential therapeutic target. Further studies are needed to elucidate the mechanisms by which SHBG may confer protection against IS.