Objective: This study assessed the antimicrobial use-related drug therapy problems (DTPs) among patients admitted to the medical ward of Wachemo University Nigist Eleni Mohammed Memorial Comprehensive Specialized Hospital (WCUNEMMCSH), Southwest Ethiopia. Methods: A hospital-based prospective observational study design was used to assess antimicrobial use-related DTPs among patients admitted to the medical ward of WCUNEMMCSH from June to August 2021. Data were collected using a structured data abstraction format. Results: In all, 128 patients admitted to the medical ward were enrolled. Among the study participants, at least one form of antimicrobial DTP occurred in 98 (76.6%) of them. The most prevalent DTPs were unnecessary drug treatment in 42 (32.8%), the need for additional drug treatment in 36 (28.1%), and non-adherence in 30 (23.4%) of the patients. There were a total of 288 antimicrobial drug orders. Ceftriaxone 120 (41.7%) and azithromycin 69 (24.0%) were the most commonly prescribed antimicrobial drugs. In multivariate logistic analysis, the length of hospital stay (adjusted odds ratio (AOR) = 2.97, 95% confidence interval (CI): 1.06–8.32; p = 0.04) and the number of diagnosed diseases (AOR = 3.10, 95% CI: 1.12–8.15, p = 0.02) were predictors of antimicrobial use-related DTPs. Conclusion: Antimicrobial use-related DTPs are common among patients admitted to the medical ward of WCUNEMMCSH. Health professionals should work together to reduce the high prevalence of DTPs among medical ward admitted patients in this hospital.