Background <p>Given the rising incidence of end-stage kidney disease (ESKD) in Sudan, assessing health-related quality of life (HRQOL) is critical for evaluating patient outcomes. This study evaluated HRQOL and associated factors in end-stage kidney disease patients in Khartoum State renal centers in Sudan.</p> Methods <p>This cross-sectional study administered the Kidney Disease Quality of Life Short Form (KDQOL-SF™) to 150 ESKD patients on maintenance dialysis for ≥ one month across 13 renal centers in Khartoum State. Data were analyzed using SPSS Statistics. Independent t-tests, ANOVA, Pearson correlation, and multiple regression analyses were conducted to assess associations. The p-value was set at 0.05 for statistical significance.</p> Results <p>The Physical (40.17 ± 9.01) and Mental (47.10 ± 9.86) Component scores significantly affected HRQOL in ESKD patients. The lowest scores were observed for burden of kidney disease (31.25 ± 38) and work status (0.00 ± 50). The SF-12 Physical Component was associated with employment status (<i>p</i> &lt; 0.001) and dialysis accompaniment (<i>p</i> = 0.011). Diabetes comorbidity affected the Mental Component (<i>p</i> = 0.017). Hospitalization frequency showed significant negative correlations with the SF-12 Mental Component (<i>r</i> = -0.249), burden of kidney disease (<i>r</i> = -0.330), effects of kidney disease (<i>r</i> = -0.303), and Kidney Disease Component Summary (<i>r</i> = -0.247). In the multiple regression model for the SF-12 Physical Component, age group was the only significant factor (<i>p</i> = 0.023).</p> Conclusion <p>Both physical and mental health domains were significantly impaired in the studied ESKD population. The lowest scores were observed for disease burden and work status. Enhancing healthcare access, addressing comorbidities, and reducing financial strain may improve outcomes. Further longitudinal and case-control studies are warranted to clarify determinants of HRQOL.</p>