Background. Patients with multiple chronic conditions often have complex medication regimes which negatively impact their health-related quality of life (HRQoL), and there is limited evidence on this topic, particularly from the resource limiting set-up. Hence, this study is aimed at assessing the impact of medication regimen complexity on HRQoL in patients with multiple chronic conditions at a university hospital in Ethiopia. Method. A cross-sectional study was conducted on adult patients who had at least two long-term diseases and were already receiving medical therapy for the relevant disorders. The validated 65-item Medication Regimen Complexity Index (MRCI) and the EuroQol-5-Dimensions-5-Levels (EQ-5D-5L) instruments were used to assess MRC and HRQoL, respectively. The Welch test for unequal variance and Fisher's exact test were used to assess the impact of different variables on HRQoL. Results. The study surveyed 416 participants, with a 98.3% response rate, the majority of whom were female (n = 267, 64.2%) and had two chronic conditions (n = 215, 51.7%). About 46.4% of patients were taking five or more medications, with a significantly higher proportion at the high regimen complexity level (P=0.001). The average MRCI score was 9.73 & PLUSMN; 3.38, indicating a high level of complexity. Patients with high MRCI scores reported more problems in mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. There was a negative correlation between the MRCI score and HRQoL as measured by the EQ-5D-Index (r = -0.175; P<0.001) and the EuroQol-Visual Analogue Scale score (r = -0.151; P=0.002). In addition, there was a statistically significant difference in the mean EQ-5D-Index (P=0.001) and EQ-VAS scores (P=0.001) across low, medium, and high MRCI levels. Conclusion. Medication regimen complexity was prevalent among patients with multimorbidity and was associated with a decrease in HRQoL. Therefore, interventions addressing medication-related issues should be a priority to improve the well-being of patients with multiple chronic conditions.