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Abstract Background Approximately 60,960 people are diagnosed with cancer each year, and more than 44,000 people die from it. Family caregivers face a range of difficulties because cancer affects many facets of life, such as nursing care, communication, financial issues, and emotional conflicts. Consequently, family caregivers are more susceptible to developing demanding physical and mental conditions. Despite these problems, cancer remains the most neglected and underfunded health problem in Ethiopia. Therefore, this study aimed to assess the caregiver burden experienced by family caregivers of patients with cancer; as well as its associated factors. Methods An institutional-based cross-sectional study was employed among 347 family caregivers of cancer patients who attended Hawassa University Comprehensive Specialized Hospital Oncology Center from May 30 to July 30, 2022. The data were checked for completeness and consistency and then coded. The coded data were entered into Epi-data version 4.6 and then exported into Statistical Package for Social Science (SPSS) version 25 for analysis. The caregiver’s burden was assessed by a short form of Zarit burden Interview. The explanatory variables, like clinical and care-related factors, were assessed by a structured questionnaire. Family caregivers’ perceptions of social support were assessed by the multidimensional scale of perceived social support. Binary logistic regression was used to assess the strength of the association between outcome and explanatory variables. Each explanatory variable was entered separately in the bivariate analysis, and a variable with a p-value less than 0.25 goes further for multivariate analysis to control the possible confounding. The statistical significance of the factors influencing the outcome variable was declared in multivariate logistic regression analysis using an adjusted odds ratio at a 95% confidence interval when a p-value