Purpose To elucidate the potential role of genetic polymorphisms of apolipoprotein E (APOE) in nonarteritic anterior ischemic optic neuropathy (NAION) and the association between APOE and NAION-induced ocular impairments. Methods A total of 73 NAION patients and 73 sex- and age-matched healthy controls were recruited for the study. Genomic DNA was isolated from peripheral blood samples. The alleles and genotypes of APOE were explored. The interaction between APOE and medical comorbidities was assessed by the multifactor dimensionality reduction (MDR) method. Among 81 affected eyes of NAION patients, an additional association study of APOE isoforms with visual impairments was carried out. Results The allele and genotype frequencies for APOE showed significant differences when comparing NAION cases and controls. Multivariate analysis adjusted for age, sex, hypertension, dyslipidemia, diabetes mellitus, cardiovascular disease, and cerebrovascular disease revealed that the epsilon 3/epsilon 4 genotype (OR = 3.86, 95% CI = 1.13-13.25, p = 0.032) and epsilon 4 allele (OR = 3.55, 95% CI = 1.05-11.99, p = 0.041) were strong independent risk factors for NAION. Compared to eyes with the epsilon 3/epsilon 3 + epsilon 2/epsilon 4 genotype, individuals with the epsilon 4/epsilon 4 + epsilon 3/epsilon 4 genotype had worse visual field defects (VFDs) and thinner macular ganglion cell complex (mGCC) thicknesses with larger focal loss of volume (FLV) and general loss of volume (GLV). Compared to epsilon 4 noncarriers, epsilon 4 carriers also tended to have more serious VFD and mGCC loss. Conclusions APOE polymorphisms conferred a significant risk of NAION and were significantly related to ocular impairments caused by NAION.