Background: Dialysis adequacy (Kt/V) remains an essential marker of hemodialysis quality; however, it does not fully capture patients’ overall well-being. Growing evidence underscores the need for a more holistic, patient-centered approach that integrates clinical efficiency with factors affecting daily functioning and quality of life (QoL). Objectives: This study aimed to identify the key determinants of health-related quality of life (HRQoL) among Polish patients undergoing hemodialysis. Methods: Seventy hemodialysis patients from a single center completed the KDQOL-36 questionnaire and provided demographic and clinical data. Statistical analyses included Pearson’s and Spearman’s correlations, as well as multiple linear regression, to determine predictors of HRQoL. Results: The mean (SD) KDQOL summary score was 60.9 (17.3). Pain (B = −15.9, p < 0.001) and the need for additional dialysis sessions (B = −10.2, p = 0.008) were the strongest independent predictors of poorer HRQoL, collectively accounting for 28.6% of variance. Longer dialysis-related transportation time (r = −0.238, p = 0.03) and longer hemodialysis vintage (r = −0.254, p = 0.03) were also significantly associated with lower HRQoL, while dialysis adequacy showed no significant effect. Conclusions: Pain, additional dialysis sessions, and longer dialysis-related transportation time are key, modifiable contributors to reduced HRQoL in Polish hemodialysis patients. These findings underscore the importance of a patient-centered approach that supplements clinical measures with interventions targeting comfort, education, and accessibility. Incorporating structured pain management and improved transport into routine nephrology practice can meaningfully improve patient QoL.