Abstract Introduction Improper disposal of medications poses a significant environmental risk on the ecosystems and human beings1. When medicines are discarded by flushing them down the toilet or throwing them in the household trash, their active components may leak into the water supply2. Aim This systematic review seeks to compile studies that examine healthcare professionals' and students' knowledge, attitudes, and practices (KAP) regarding medication disposal. It also aims to explore recommendations and barriers related to appropriate medication disposal. Methods A systematic review was conducted by adhering to guidelines outlined in Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020 and the Joanna Briggs Institute. The primary outcome is to measure the levels of the healthcare staff and students' knowledge, as well as their attitudes, and practices about disposal of unwanted medications. Authors included qualitative, quantitative, and mixed-method primary research studies. Participants included pharmacists, doctors, nurses, and both undergraduate and postgraduate medical, pharmacy, and nursing students due to their significant involvement with medication and its disposal in healthcare settings. Data extraction was conducted by four of the researchers independently. The study details were categorised into three main domains i.e., knowledge, attitude, and practice using the KAP model. Other relevant information was also extracted, thematically, such as challenges and recommendations. Ethical approval was not required as this systematic review used previously published data. Results 37 studies from 18 countries (21 from Asia, 7 from the US, 5 from Africa, and 2 each from the EU and South America) met the inclusion criteria. 86.5% (n=32) investigated participants' knowledge of medication disposal. Although there is a good level of awareness about the environmental impacts, there are significant gaps in knowledge regarding correct disposal methods, available services, guidelines, and training. 30 studies explored participants' attitudes toward medication disposal. The results indicate a generally positive attitude towards the need for environmentally safe disposal practices. 35 studies evaluated participants' practices in relation to medication disposal. Although there was generally a positive attitude and some understanding of appropriate disposal methods, majority of the participants do not follow the practice guidelines, especially outside healthcare settings. This inconsistency may be due to numerous factors such as inadequate practical training, limited resources, or unclear guidelines. Discussion/ Conclusion Overall, it was found that while healthcare staff and students have fair knowledge and positive attitudes toward medicine disposal, their actual practices are lacking. One significant challenge identified is the limited awareness about proper disposal methods coupled with a lack of established services or guidelines in many regions. Even in cases where take-back programs are available, they often face issues with accessibility. To tackle these challenges, it is suggested by the studies that governmental bodies should establish and enforce clear policies on medication disposal while also expanding educational initiatives to increase understanding among healthcare professionals and students about appropriate disposal methods. Furthermore, improving access to take-back programs is crucial for ensuring safe medication disposal and minimising potential environmental and health hazards.