BACKGROUND: Pharmaceutical waste (PW) generated in health facilities includes expired or unused medications, contaminated materials, and other pharmaceutical residues from diagnosis, treatment, immunization, compounding, and manufacturing. PW management (PWM) is critical for environmental protection and public health. Therefore, this study aimed to evaluate management of PW at hospitals and community pharmacies in Bahir Dar and Gondar cities, Ethiopia. METHODS: A facility-based cross-sectional study was conducted in hospitals and private pharmacies in Gondar and Bahir Dar cities from July 2023 to September 2023. Hospitals and pharmacies were selected based on their significance as major urban centers in the Amhara region of Ethiopia. About 208 pharmacies and drug stores, both public and private, that were open during the data collection period and one pharmacy professional from each dispensary were included in the study. SPSS version 26.0 was used for analysis. Descriptive results are reported as the means with standard deviations (SDs), frequencies, and percentages. Binary logistic regression was used to identify predictors of PWM knowledge. A P value of 0.05 was considered statistically significant during the data analysis. RESULTS: Most participants (59.6%) had good knowledge about PWM. Experience (AOR = 2.86, 95% CI: 1.26, 6.48) and regular PWM training (AOR = 3.60, 95% CI: 1.73, 7.49) were significantly associated with good knowledge about PWM. PWM practices were rated similarly by the participants, with good and poor scores of 52.9% and 47.1%, respectively. Experience (AOR = 3.33, 95% CI: 1.49, 7.47) and working at a hospital (AOR = 5.19, 95% CI: 1.95, 13.83) were significantly associated with good practices toward PWM. Most participants' facilities had different infrastructures for PWM, such as PW collection containers (90.9%), clean containers (88%), color-coded and labeled containers (73.6%), burial pits without liners (54.8%), personal protective equipment (79.3%), and access to municipal-level landfills (62%). However, only 47.6% of the participants' facilities had an incinerator for the disposal of ashes. CONCLUSION: Most participants had good knowledge and practices related to PWM. Experience with and training about PWM were significantly associated with the good knowledge of participants about PWM. Additionally, experience and working in hospitals were also significantly associated with the good practices of participants toward PWM. Participants who had more exposure to PWM practices demonstrated better adherence, and those working in hospitals exhibited superior PWM practices compared to those in community pharmacies. Improper disposal of pharmaceutical waste threatens environmental health, contaminating water and soil, harming ecosystems, and posing risks to vulnerable populations. To address this, regular training for pharmacy personnel on safe disposal and segregation is essential. Additionally, investing in infrastructure like incinerators and proper landfills is crucial for sustainable PWM, mitigating associated public health risks.