Objective: To evaluate and analyze the prevalence, spatial distribution characteristics, and influencing factors of anisometropia among school-aged children and adolescents aged 6-18 across 14 prefectures in Xinjiang, thereby providing a scientific foundation for formulation of regional eye health intervention strategies. Methods: A cross-sectional study design was employed, including 64,277 students from primary, middle, and high schools in 14 prefectures of Xinjiang. Data on demographic characteristics, refractive status, and geographical distribution were collected. Refractive status was assessed using spherical equivalent (SE). Myopia was defined as SE ≤ -0.50 D, and anisometropia was defined as an interocular SE difference ≥ 1.0 D. Moran's I analysis was used to evaluate the spatial distribution of anisometropia prevalence. Additionally, univariate and multivariate regression analyses were conducted to identify risk factors for anisometropia. Results: The overall prevalence of anisometropia was 17.9% (95% CI: 17.6%-18.2%). The prevalence was higher among females (18.8%) compared to males (16.9%), and higher among Han Chinese (23.9%) than among Uyghurs (11.7%) and other ethnic groups (18.4%) (P<0.001). The prevalence of anisometropia showed a spatially clustered distribution (Moran's I = 0.450, P= 0.043, Z-score = 2.026) , with notable regional variations. Changji had the highest prevalence (24.1%), while Kizilsu Kirghiz Autonomous Prefecture had the lowest (7.9%). Urban areas (19.0%) had a higher prevalence than rural areas (15.6%), and northern Xinjiang (19.9%) had a higher prevalence than southern Xinjiang (13.5%) (P<0.001). The prevalence of anisometropia was positively correlated with age, increasing from 9.8% at age 6 to 22.4% at age 18. Multivariate regression analysis showed that female gender, residing in northern Xinjiang, myopia, and older age were independent risk factors for anisometropia. Conclusions: The prevalence of anisometropia among school-aged children and adolescents in Xinjiang is relatively high, showing a spatially clustered distribution with significant demographic and regional disparities. Female gender, residing in northern Xinjiang, myopia, and older age are independent risk factors for anisometropia. It is recommended to enhance vision screening and implement early intervention for high-risk populations.