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Abstract Aims This study aimed to evaluate the prescription frequency of potentially harmful prescription drugs as defined in current heart failure guidelines among elderly patients with a diagnosis of heart failure with reduced ejection fraction and their association with clinical outcomes. Methods and results We used the Centers for Medicare & Medicaid Services data from a nationally representative 5% sample for the years 2014–2016 to identify patients admitted to acute care hospitals with a primary diagnosis of heart failure with reduced ejection fraction. The primary exposure was filling a prescription for a potentially harmful drug. Potentially harmful drug fills were treated as a time‐dependent covariate to examine their association on readmission and mortality. A total of 8993 patients met study criteria. Potentially harmful drugs were prescribed in 1077 (11.9%) patients within 90 days of discharge from the heart failure hospitalization. Non‐steroidal anti‐inflammatory agents were the most frequently prescribed potentially harmful drug (6.7%) followed by calcium channel blockers (4.7%), thiazolidinedione (0.59%), and select antiarrhythmic (0.33%). Factors independently associated with potentially harmful drug prescription were female gender, Hispanic ethnicity, severe obesity, among others. In the multivariable Cox model, the prescription of a potentially harmful drug was associated with an increased risk of readmission (hazard ratio 1.14; 95% confidence interval 1.05–1.23, P