Background: COVID-19 has caused great changes in all aspects of life which affected all people especially vulnerable groups such as children with disabilities (CWD) and their families. Objective: This study aimed to examine the challenges facing caregivers of CWD during the pandemic, and to explore these challenges from various physical, social, psychological, and financial aspects. Methods: A cross-sectional design was conducted in Palestine, a total of 130 caregivers of CWD completed a survey consisting of demographic and clinical characteristics questionnaire and the short version of the burden scale for family caregivers (BSFC-s) between March and May 2021. Results: Most of the caregivers were mothers (76.9%), the mean age of the children was (6.09 ± 3.43 years). The majority (88.5%) of the caregivers felt physically exhausted, about (75.4%) had decreased living standards, and (86.2%) indicated that caregiving is taking their strength. A high burden score was recorded, the mean BSFC-s score was 20.17 ± 5.57. Significant differences in BSFC-s scores were recorded based on the type of disability, and child’s ability to take care of oneself, P < .05. The total scores of the BSFC-s were positively correlated with the physical, social, psychological, and financial challenges facing the caregivers ( P < .001). Conclusions: COVID-19 has caused increased burdens on the caregivers of CWD and a negative impact on the child’s mobility accompanying a lack of access to health and rehabilitation services. Vital factors are to be considered in developing strategic health and rehabilitative plans for promoting better care for caregivers and their CWD during lockdown restrictions time.