Background: Childhood obesity tracks into adulthood and is a risk factor for non-communicable diseases such as cardiovascular diseases and diabetes. The relationships between socioeconomic status (SES) (including food security, financial stability, and living conditions) and obesity among children have been well established. However, there is limited research on the heterogeneity of the role of food insecurity or insufficiency and neighborhood deprivation (ND) on obesity risk in children. We aimed to investigate the moderating effect of food insecurity in the association between ND, health insurance, race/ethnicity, and Body Mass Index (BMI) among children aged 3-11 years old. Methods: For this cross-sectional study of 223,653 children aged 3-11 years who were members of Kaiser Permanente in Southern California, weight and height were collected during routine annual medical visits and extracted from electronic health records. ND index (NDI) was based on patients’ addresses using 2021 regional data. Higher indices represent a higher deprivation. The risk of food insecurity was assessed using the Hunger Vital Sign™ tool on the well-child visit questionnaire. A multivariate linear regression analysis was performed with the absolute distance from the median BMI-for-age and sex based on the 2000 CDC growth charts. Models included age, sex, race/ethnicity, state-subsidized health insurance, self-reported risk food insecurity, and 2-way interaction terms for NDI and state-subsidized health insurance with food insecurity. Results: The cohort included children with a mean age of 7.9 years (SD 2.4), males (51.2%), Hispanics (50.3%), living with obesity (24.1%), resided in neighborhoods above the average deprivation (39.6%), and were enrolled in state-subsidized health insurance (25.6%). The risk of food insecurity and insufficiency were reported at 5.0% and 3.3%, respectively. In adjusted models, a higher NDI quintile, state-subsidized health insurance, race/ethnicity, and food insecurity were all associated with a higher BMI (p<0.0001). Food insecurity also moderated the association between NDI and BMI (p = 0.0244) and between state-subsidized health insurance and BMI (p = 0.0034). The effect of food insecurity was highest among those with the least ND and with private health insurance. In a separate model, food insecurity had no moderating effect in the association between race/ethnicity and BMI (p = 0.1). Conclusion: Food insecurity showed a moderating effect on high BMI risk among children in higher deprived neighborhoods and enrolled in state-subsidized health insurance. This study highlights the possible effects of food insecurity on obesity among children regardless of race/ethnicity. Future studies are recommended to investigate the moderating role of food insecurity in health outcomes, specifically obesity-associated conditions among children with low SES.