|Uganda has made significant progress in implementing quality management systems (QMS) in clinical laboratories, resulting in 38 accredited facilities. Despite these advancements, challenges persist, impeding the attainment of ISO 15189 accreditation for several laboratories in Teso sub-region, Uganda. This study aimed to identify and assess non-conformances and challenges faced during QMS implementation towards ISO 15189 accreditation in selected clinical laboratories in Teso sub region, Uganda. Audit reports from 3 consecutive audits carried out within the last 5 years (2017-2021) of implementation for each of the selected laboratories was reviewed to identify the non-conformances. The non-conformances were categorized into major and minor and their frequencies of occurrence attained. In-depth interviews with consenting participants was conducted to identify the challenges that led to the different non- conformances encountered during this process and how they affect the accreditation process. The findings revealed a total of 553 non-conformances (NCs) throughout the study period across all five selected clinical laboratories. Among these, 50.8% were classified as major non-conformances, while 49.2% were minor. The most prevalent areas of non-conformance were related to the quality system essentials, such as documents and records, facilities and biosafety, equipment, process control, organization, and personnel. Frequencies of major and minor non-conformances varied among the study laboratories during their respective audit periods. Analysis of interview data uncovered key challenges, including limited access to funds, high workload, protracted and rigid procurement processes, constrained budget allocations, staff demotivation due to inadequate remuneration, communication gaps, non- compliance with documentation processes, and a lack of awareness about the benefits of QMS. The study identified a high prevalence of major non-conformances within the selected clinical laboratories in the Teso sub-region of Uganda, notably in the essential aspects of Documents and Records, Facilities and Biosafety, Equipment, Process Control, and Organization and Personnel. This emphasizes the need for targeted corrective actions and continuous monitoring. Laboratories in this sub-region should advocate for sufficient resources and supportive policies, with active involvement from upper management. Therefore, continuous mentorship, increased budget allocations, and employment of more personnel are necessary to overcome their challenges and advance towards effective quality management systems.