<p>Healthcare waste poses significant risks to human health and the environment when improperly managed. In low-income countries such as Ethiopia, healthcare waste management remains a major public health concern, particularly among waste handlers who are directly exposed during waste handling processes. This study aimed to assess healthcare waste management practices, associated factors, and barriers among waste handlers in healthcare facilities in Gondar City, Northwest Ethiopia. An institution-based mixed-methods study was conducted from May 30 to June 30, 2025, among 372 waste handlers selected using multistage sampling techniques. Quantitative data were collected using structured questionnaires and analyzed using Bivariable and multivariable logistic regression analyses. Qualitative data were collected through a descriptive phenomenological approach and analyzed thematically. The prevalence of good healthcare waste management practices was 39.4%(95% CI:34.3,44.5). Type of healthcare facility, work section, training, disposal system type, availability of personal protective equipment (AOR:5.63;95%CI:2.64,12.02), knowledge (AOR:4.44;95%CI:2.38,8.26), and attitude (AOR:7.86;95%CI:4.05,15.28) were significantly associated with healthcare waste management practices. Qualitative findings revealed major barriers including shortage of human resources, poor disposal systems, weak institutional supervision and also insufficient availability of personal protective equipment was a key barrier that limited waste handlers’ ability to perform their work safely and effectively. Healthcare waste management practices among waste handlers in Gondar City were inadequate. Strengthening regular training programs, ensuring adequate provision of personal protective equipment, improving waste disposal systems, and enhancing institutional supervision are essential to promote safe waste management practices and reduce occupational health risks.</p>