Polypharmacy among older patients has been associated with a decline in their quality of life. We aimed to assess the medication-related quality of life (MRQOL) among older patients with polypharmacy at Gondar University Hospital, Gondar, Ethiopia. A prospective cross-sectional study was carried out among 150 elder patients who had visited the internal medicine ward and ambulatory ward of Gondar referral hospital from March 25 to May 15, 2017, using a validated scale, Medication-Related Quality of Life Scale version 1.0 (MRQoLS-v1.0). A total of 150 older patients with polypharmacy participated in the study with a mean age of 70.06±5.12, andtwo-thirds of the participants (67.3%) were female. The overall prevalence of poor quality of life due to polypharmacy in the current study was found to be three fourth (75.3%) of the participants. Regarding the severity of impairment in MRQoL, Univariate analysis revealed that frequency of hospital visits (COR = 1.34, 95% CI, 1.02-1.77) and medication number (COR = 1.94, 95% CI, 1.33, 2.8) had a statistically significant positive association with the likelihood of having a severe impairment.The multivariate analysis also showed that one unit increase in the number of hospital visits (AOR = 1.45, 95% CI, 1.040-2.024) and medications greater than 5 (AOR = 1.91, 95% CI, 1.29, 2.84) increases 1.45 and 1.91 times the likely hood of posing severe impairment of MRQoL, respectively. As far as poor MRQoL quality of life is concerned, multivariate analysis did not show any significant association between the poor MRQoL;and Sociodemographic and clinical data of patients. The poor QoL associated with medication was very high in this study. Deprescribing should be sought by the health care providers to optimize drug therapy and minimize the polypharmacy related poor quality of life.