The main objective of this research is to explore which factors best predict the occurrence of burden on primary caregivers of children with cerebral palsy (CP). Understanding these factors enables the identification of those caregivers at risk of having their physical and psychological health adversely affected, and the implementation of intervention strategies to reduce the negative impact of caring on parents of children with chronic medical conditions. The study sample consisted of a total of 62 caregivers (89% women) aged between 30 and 54 years (Mean = 41.98, SD = 5.64). CP affected children were aged between 1 and 17 years (Mean = 7.69, SD = 4.18) and the average degree of disability (% reflected in the medical record assessed by the Ministry of health, social services and equality of Spain) was 77.098 (scale of 100) (SD = 14.62). A burden model was constructed based on multiple linear regressions. The model included the following variables: degree of disability, depression (assessed by Beck Depression Inventory-II) and self-efficacy (measured by the Revised Scale for Caregiving Self-Efficacy). The regression model explained 40.9% of the total variance. It was found that self-efficacy had a negative linear association with burden, while the degree of disability and depression showed a positive linear association. The most important predictors of caregiver burden were degree of disability, depression and self-efficacy. For this reason, we believe that it is necessary to develop interventions to reduce depression and enhance self-efficacy in parents of children with CP as one of the primary objectives for minimizing the burden on caregivers of disabled children.