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Abstract Background End-Stage Kidney Disease, the most severe form of chronic kidney disease, is fatal if not treated by renal replacement therapy. Thus, patients with End-Stage Kidney Disease depend on hemodialysis as a lifesaving treatment for the remainder of their lives. However, the health-related quality of life (HRQOL) of patients on hemodialysis is much more underappreciated in resource limited countries. Methods A hospital based cross-sectional study was conducted in Addis Ababa, Ethiopia, from August 01 to October 31, 2019. All patients who were on hemodialysis in five randomly selected public and private hospitals (n = 125) were included in the study. Data were administered by trained nurses by using a standardized Kidney Disease Quality of Life questionnaire. Clinical data were extracted from the patients’ medical charts. HRQOL was categorized as low, if the overall mean score was ≤ 50, or as high, if the overall mean score was > 50. Factors associated with lower HRQOL were identified by multi-variable binary logistic regression analysis and expressed by adjusted odds ratio (aOR) and its respective 95 % confidence interval. Results The mean age of the study participants (n = 125) was 50.33 years (± 15.07) and more than two-thirds (68.8 %) of the participants were males. The mean score of HRQOL was 49.08 ± 11.09, with 48.0 % (95 % CI: 42.2 − 54.5 %) of them had lower HRQOL. Unemployed patients (aOR = 2.40, 95 % CI: 1.10–5.90) and patients who had hemodialysis 2 times per week (aOR = 1.71, 95 % CI: 1.07–3.83) had lower HRQOL. Elderly patients had higher odds of having lower mean score on the burden of kidney disease (aOR = 2.07; 95 % CI 1.18–4.13) as compared to the younger patients. Conclusions Nearly half of the patients with ESKD on hemodialysis had lower overall HRQOL which is associated with their unemployment status and frequency of hemodialysis per week. Elderly patients had lower mean score of burden of kidney disease. Therefore, quality of life of patients with chronic dialysis should be given special attention during the patients’ care. Measures should be taken by the government to ensure accessibility and affordability of the hemodialysis services in the country.