End-stage renal disease (ESRD) presents a significant global health challenge, with hemodialysis (HD) being the primary treatment option. HD patients are prone to complications such as protein-energy wasting (PEW), inflammation, and cardiovascular disease (CVD). The imbalance in the ratio of copper (Cu) to zinc (Zn) has been implicated in the development and progression of these conditions. However, little is known about the association between the Cu/Zn ratio and these metabolic parameters in Ethiopian hemodialysis patients. This study aimed to evaluate the association of the Cu/Zn ratio with protein-energy wasting, inflammation, and CVD susceptibility in hemodialysis patients at St. Paul Hospital Millennium Medical College (SPHMMC), Addis Ababa, Ethiopia. A cross-sectional study was conducted for three months, involving 42 hemodialysis patients and 20 healthy individuals as controls. Serum Cu and Zn levels were measured using inductively coupled plasma mass spectroscopy (ICP-MS), and the Cu/Zn ratio was calculated. PEW was assessed through anthropometric measurements and biochemical markers. Inflammation levels were determined using C-reactive protein (CRP) while CVD risk factors were evaluated. The correlation between the Cu/Zn ratio and markers of PEW, inflammation, and CVD risk factors in hemodialysis patients was examined. The Statistical Package for Social Science (IBM SPSS version 20) was used for the data analysis. The study revealed that most hemodialysis patients (64.2%) exhibited an elevated Cu/Zn ratio compared to healthy controls. The Cu/Zn ratio showed a significant inverse correlation with serum albumin levels and triceps skinfold thickness and CRP indicating a relationship with PEW and Inflammation. Furthermore, a moderate positive correlation was observed between the Cu/Zn ratio and basal systolic blood pressure, a well-known CVD risk factor. Hemodialysis patients demonstrated an elevated Cu/Zn ratio, associated with PEW, inflammation, and increased cardiovascular disease risk factors. Monitoring and managing these imbalances are crucial for improving hemodialysis patients' health outcomes.