Objective The importance of antimicrobial stewardship is increasingly highlighted in this age of antimicrobial resistance. A better comprehension of adverse drug events (ADEs) can promote the appropriate use of antibiotics. We aimed to quantify the incidence of ADEs associated with broad-spectrum systemic antibiotics in a hospital setting. Methods We conducted a six-month prospective, observational study at Osaka University Hospital to describe the incidence of ADEs in patients hospitalized in general wards undergoing treatment with broad-spectrum antibiotics [carbapenems, piperacillin/tazobactam (PIPC/TAZ), and anti-methicillin-resistant Staphylococcus aureus agents]. The occurrence of ADE was defined as any cardiac, gastrointestinal, hepatobiliary, renal, neurologic, hematologic, dermatologic, or musculoskeletal manifestation after 48 hours or more of systemic antibiotic therapy. Results The 3 most frequently prescribed antibiotics were PIPC/TAZ (242 cases), meropenem (181 cases), and vancomycin (92 cases). Of 689 patients, 118 (17.1%) experienced ADEs, including gastrointestinal (6.4%), hepatobiliary (4.2%), dermatologic (2.5%), and renal (2.3%) manifestations. Patients treated with PIPC/TAZ, meropenem, doripenem, vancomycin, daptomycin, and teicoplanin developed ADEs at rates of 20.7%, 16.0%, 15.4%, 19.6%, 11.8%, and 10.9%, respectively. Conclusion Our study provides a quantitative value for the incidence of ADEs associated with broad-spectrum antibiotics in clinical practice. To optimize patient safety, clinicians need to be aware of the risks associated with antibiotic administration.