Background. Accumulation of unused and expired medicines at home is a source of environmental hazards and public health problems due to lack of awareness on appropriate medicine disposal methods. Therefore, the study was conducted to assess the knowledge, attitude, and practice of unused and expired medicine disposal among patients visiting Ayder Comprehensive Specialized Hospital. Methods. A descriptive cross-sectional study was conducted among 384 patients who visited Ayder Comprehensive Specialized Hospital outpatient pharmacy from April to June 2019. Convenience sampling was used to recruit the participants, and data was collected by a face-to-face interview using a structured questionnaire. The data were entered and analyzed by using SPSS version 21.0. Descriptive statistics on sample characteristics was computed, and results were presented in the form percentage using table and statements. Results. Out of the 384 respondents included in the study, 205 (53.4%) of them were males. More than half (199 (51.8%)) of the respondents did not correctly knew about medicine waste, and 233 (60.7%) of them did not have any prior information regarding medicine waste disposal instruction. But 351 (91.4%) of the participants correctly responded that inappropriate unused and expired medicine disposal can cause environmental harm. Above half (218 (56.8%)) of the respondents “agreed” about the potential risks related to having unused/expired medicines at home, and 206 (53.6%) of them “strongly agreed” that children are more vulnerable. One hundred fifty-nine respondents had unused/expired medicines in their homes. The most commonly used disposal practice for unused medicines were throwing them in a household trash as reported by 297 (77.3%) followed by flushing unused medications in toilet/sink 152 (39.6%). Throwing them away in household garbage and flushing them in toilet/sink were also the most commonly preferred disposal practice for expired medicines. Conclusion. The majority of the study participants dispose unused and expired medicine in household garbage and toilet/sink. This is against the recommendations of both national and international policies and guidelines on safe and appropriate pharmaceutical waste disposal.