Background Medication related problems in cardiovascular disease patients, especially among heart failure patients were found to be high. Medication related problem is a critical problem to provide high quality health care service for the patient which is associated with high mortality, complication, prolonged hospital stay, compromised quality of life and increase health care cost. Objective To determine medication related problems and its predictors in hospitalized heart failure patients at Jimma Medical Center, from May 30, 2019 to November 28, 2020 Methods A prospective interventional study was conducted among heart failure patients from May 30, 2019 to November 28, 2020 at Jimma Medical Center. Medication related problems were sorted based on Pharmaceutical care network Europe drug classification tool version 9.0. Patient’s specific data was collected using questionnaire. The data were coded, cleaned, and entered into Epidata version 4.6 and exported to SPSS version 25.0 for analysis .Binary Logistic regression was used to identify independent predictors of medication related problems occurrence. Variables having P-values < 0.05 were considered statistically significant Results A total of 384 heart failure patients were included in the study. The mean (SD) age was 49.06 ± 17.79. Two third of study participants had at least one medication related problem. A total of 483 MRPs were identified among 231(60.15%) patients. Treatment effectiveness related problem (55.48%) was the most common observed medication related problems. Alcoholism (AOR; 3.25, 95% CI (1.46–7.23), prolonged hospital stay [AOR = 3.67, 95%CI= (1.85–7.27)]; comorbidity [AOR = 2.88, 95%CI= (1.47–5.66)] and polypharmacy [AOR = 3.07, 95%CI= (1.57–5.99) were the independent predictors of medication related problems. Conclusion The prevalence of medication related problem was high among heart failure patients. Alcoholism, prolonged hospital stay, comorbidity and polypharmacy were the predictors of medication related problems. Hence, to overcome these problems, clinical pharmacists, physicians and other health care professionals have to work in collaboration.