INTRODUCTION: Mothers of children with chronic diseases, as the main caregivers, face the care burden. The care burden of mothers can affect their adaptive behaviors and lead to the use of inappropriate adaptive behaviors. This study was conducted to determine the relationship between the caregiving burden and adaptive behaviors of mothers of children with chronic diseases. METHODS: In this descriptive-analytical cross-sectional study, 238 mothers of children with chronic diseases participated by the convenience sampling method. Data collection tools included a demographic information questionnaire, a zarit care burden questionnaire, and a health matching questionnaire for parents. Data were analyzed using descriptive statistics, t-test, ANOVA, and Pearson analysis in SPSS software version 26. RESULTS: The majority of mothers had a mean age of 34.6 ± 7.6 years. The caregiving burden on the mothers of children with chronic diseases was high (21.95 ± 7.76) and most of the mothers had favorable adaptive behaviors in facing their child's illness (95.14 ± 17.15). The most intensity of the significant correlation was in the pattern of "family integrity and optimization of the situation" (P <
0.001, r = -0.434). The mother's illness (P = 0.009, β = 2.874), care of the child with chronic disease only by the mother (P = 0.008, β = 3.142), and immunodeficiency disease of the child (P = 0.021, β = 4.456) positively predicted the caregiving burden. CONCLUSION: These findings help healthcare systems plan supportive and educational programs for decreasing the caregiving burden and increasing adaptive behaviors in mothers of children with chronic diseases. LAY SUMMARY: A cross-sectional study was conducted to determine care burden and adaptive behaviors in mothers with chronically ill children. The results showed that mothers' care burden was high and significantly related to their behavior and adaptation. Mothers had favorable adaptive behaviors.