Background: Mothers with chronic diseases may have spillover effects on their children. Objective: The aim of this study was to estimate the spillover effects of mothers with chronic disease on their children’s health-related quality of life (HRQOL) and behavior. Method: A cross-sectional study was conducted on 255 mother–child pairs (130 boys and 125 girls, mean age 8.4 years) from low-income Chinese families. We asked the mothers to self-report any doctor-diagnosed chronic diseases, and evaluate their children’s HRQOL and behaviors with the Child Health Questionnaire-Parent Form-50 (CHQ-PF50) and the Strengths and Difficulties Questionnaire (SDQ), respectively. Multiple linear regression analysis was conducted to assess the independent spillover effect of maternal chronic disease on children’s HRQOL and behaviors, with adjustment for confounders. The differential impact of maternal physical and mental diseases was also investigated. Results: Over one-third of mothers (n = 88, 34.5%) reported one or more doctor-diagnosed chronic diseases. Multiple linear regression analysis showed that children of mothers with chronic diseases had significantly lower CHQ-PF50 scores in the parental impact–time, parental impact–emotional, and family activities subscales and psychosocial summary scores, as well as more hyperactive and inattentive problems measured by SDQ after adjustment for confounders. Maternal mental and physical disease showed a differential impact on children’s HRQOL and behavior. Conclusions: Chronic disease in mothers might exert adverse effects on their children’s HRQOL and behaviors. The effects could differ by maternal physical or mental disease status. Special attention and support should be paid to children of mothers with chronic disease as these children are at an increased risk of poor HRQOL and problematic behaviors.