Background: The responsibilities perceived by caregivers of children with chronic diseases can impose significant burden on their physical, emotional and mental well-being. Objective: To explore the burden of caregivers of children with chronic illnesses at a tertiary-care health facility in southern Nigeria, in order to devise effective ways of reducing them. Methodology: It was a descriptive cross-sectional survey amongst parents/caregivers of children with chronic illnesses in the Children’s Outpatient clinics /wards and emergency room, who presented for care and/or follow-up visits between October and December 2020. A validated Caregiver Burden Scale (CBS) that assesses the level of burden in five domains: general strain, isolation, disappointment, emotional involvement and environment, was used to obtain data. Caregivers’ and the children’ socio-demographic characteristics were also ascertained and compared with the level of burden. Data were analyzed using SPSS version 25.0. A p-value of < 0.05 was considered significant. Result: A total of 109 caregivers completed the questionnaire. Half (n=55; 50.5%) of the caregivers were aged 30-39years; 88 (80.7%) were females; 58 (53.2%) had post-secondary education and 51 (46.8%) were self-employed. Of the 109 children studied, 70 (64.2%) were males and the commonest diagnosis was sickle cell anaemia (SCA) (n=62; 56.9%) followed by Human Immunodeficiency Virus (HIV) disease (n=35; 32.1%). The age at diagnosis was 1-5years in 70 (64.2%) of cases while 76 (69.7%) of them had received care for 1-5years. The mean caregiving burden score was highest in disappointment (2.0) and lowest in the domain of isolation (1.5), while the overall mean score was 1.7 (SD=0.6). There was a statistically significant relationship between the caregivers’ age and all the domains studied except the general strain, while the other socio-demographic variables had varying significance with the different domains of burden. Conclusion: Severe burden of caregiving was experienced by more caregivers in the domains of disappointment and general strain while the isolation domain experienced the lowest frequency of caregivers with severe burden. Improving social support and advocacy to stakeholders, including the government to take over the financing of medical expenses of children with chronic diseases will reduce the burden of care experienced by their caregivers.