Background: Few studies have been conducted on the burden of care in caregivers of children with chronic illnesses. This study investigated the burden of care and associated factors in first-degree caregivers of children and adolescents with chronic conditions. Methods: A cross-sectional study was conducted from June to September 2017 on 385 first-degree caregivers of children and adolescents with chronic disorders. Data were collected using the Zarit burden inventory which assesses the caregiver burden in physical, psychological, economic, and relational areas and has a total score from 0 to 88. Scores 61-88, 41-60, 20-40, and <20 indicate severe, moderate, mild, and no burden. Data were analyzed using descriptive statistics and Chi-Square, Fisher's exact tests, t-test, analysis of variance, and multiple regression analysis. Results: The mean age of the caregivers and children were 38.20±8.04 and 8.90±4.90 years, respectively. Also, 33 (8.5%), 135 (35.1%), and 181 (47%) of the caregivers suffered from severe, moderate, and mild burden, and only 9.4% perceived no burden. The mean caregiver burden scores were significantly different in terms of their education (P<0.001), job status (P=0.04), financial status (P<0.001), family size (P<0.001), numbers of children (P<0.001), numbers of children with chronic illnesses (P<0.01), type of supportive resources (P=0.004), and children's education (P<0.01), type of disease (P<0.001), numbers of diseases (P<0.001), and interval of medical visits (P<0.001). Conclusion: Caregivers of children and adolescents with chronic disease are under pressure. Our study showed a number of factors influencing caregiver burden. Health care providers should plan family-centered care plans to decrease the burden of care in caregivers of children with chronic conditions.