Stroke is the second leading cause of death and a major contributor to disability worldwide, with the highest prevalence in developing countries. Ischemic stroke (IS) is a complex disease resulting from genetic and environmental interactions. The present work is a pilot study exploring the association of estrogen receptor-α (ESR1) and aryl hydrocarbon receptor (AHR) SNPs with IS in a small Egyptian population of IS patients. Sixty IS patients and 60 matched healthy controls were included in this case–control study. Genotyping of ESR1 PvuII (rs2234693), ESR1 XbaI (rs9340799), and AHR rs2066853 SNPs was performed using real-time PCR. ESR1 PvuII TC and CC genotypes were associated with IS (odds ratio (OR) = 2.821, 95% confidence interval (CI) = 1.204–6.609, p = 0.017, and OR = 9.455, 95% CI = 2.222–40.237, p = 0.002, respectively), and TC genotype in female IS (OR = 4.018, 95% CI = 1.117–14.455, p = 0.033). Additionally, ESR1 XbaI GA and GG genotypes were associated with IS (OR = 2.833, 95% CI = 1.190–6.749, p = 0.019, and OR = 34.000, 95% CI = 6.965–165.980, p < 0.001, respectively), and the AG and GG genotypes in male IS (OR = 3.378, 95% CI = 1.103–10.347, p = 0.033 and OR = 22.8, 95% CI = 2.580–201.488, p = 0.005, respectively) and the GG genotype in female IS (95% CI = 7.259–1115.914, p < 0.001). ESR1 PvuII and XbaI haplotypes C—A, T—G, and C—A increased the risk of IS in both genders, in male IS, and in female IS apart from C—A. The AG genotype of AHR rs2066853 was associated with male IS (OR = 6.900, 95% CI = 2.120–22.457 p = 0.001). ESR1 PvuII, ESR1 XbaI, and AHR rs2066853 SNPs are associated with IS in Egyptians. However, this is a small sample, and the findings should be replicated in a larger population.