Background Protein-energy wasting is a major issue in patients with chronic kidney disease (CKD), adversely affecting morbidity, mortality, functional activity, and quality of life. Assessment of nutritional status in CKD patients is important to ensure patient’s normal protein stores and avoid metabolic complications. However, in Ethiopia, there were very few studies done to assess the prevalence of protein-energy wasting (PEW) and its associated factors among CKD patients. Objective To assess protein-energy wasting and associated factors among chronic kidney disease patients at adult OPD St. Paulo’s Hospital Millennium Medical College, Addis Ababa Ethiopia. Materials and Methods An institution-based cross-sectional study was conducted from March to April 2019. Data were collected using a structured interviewer-administered questionnaire and anthropometric measurements, and laboratory data were collected from patient files. Data were entered into Epi-data version 3.1 and analyzed using SPSS version 20. Both bivariate and multiple logistic regression analyses were performed to identify associated factors. P values <0.05 were considered to declare statistical significance. Results In this study, 274 respondents were interviewed with a response rate of 100%. The prevalence of protein-energy wasting in CKD patients was 23.4%. Chronic kidney disease patients at age ≥65 years were seven times more likely to have protein-energy wasting as compared to patients aged 18–34 years [AOR=7.0, 95% (CI: 2.4, 20.5)]. Patients who had a history of anorexia were 5.2 times more likely to have protein-energy wasting as compared to those who had no history of anorexia [(AOR=5.2, 95% (CI: 2.7, 10.3)] and were significantly associated with the risk of having CKD. Conclusion The prevalence of protein-energy wasting among CKD patients was high and associated with age, physical activity, history of anorexia, and CKD stages. Interventions that address nutritional problems and lifestyle factors in CKD patients need to be implemented together with medical treatment.