One of the cornerstones of the current approach to malaria control is the provision of prompt and effective malaria treatment. This requires the regular updating of malaria guidelines and their dissemination to all tiers of the health care delivery system and a sound monitoring and supervision system. Although Artemisinin- based combination therapy (ACT) and rapid diagnostic test (RDT) has improved malaria case management substantially, the development and spread of antimalarial resistance may have dire consequences for the recent achievements in malaria control if health care providers fail to adhere to standard diagnostic and treatment guidelines. A mixed study design was used on 422 patient charts and 10 key informants. Two health centers in Arba Minch Zuriya woreda were purposely selected for this study because they are found in a malaria-endemic area and have a higher catchment population. The overall level of adherence in this study was 63.3%. Health providers fail to add primaquine as a first-line treatment for malaria infection in half(50%) of the cases. Eight (6.8%) of the patients were still given Artemether-Lumefantrine and 4 (3.4%) were given chloroquine even if they were tested negative for malaria infection by microscopy. Lack of a refresher training on malaria guideline, antimalarial and reagent stock out, lack of regular supervision, limited access to the updated guideline, and negligence of health care workers were major factors affecting the adherence of health care workers to national malaria diagnosis and treatment guideline. Overall adherence was high compared to many other studies in different African countries but an inappropriate prescription practices wastill largely observed. This could pose a big threat considering the recent spread of HRP2 gene deletion in Ethiopia which can be up to 50% in some regions. A refreshment training on the guideline and regular supervision to evaluate improvements followed by a timely feedback is recommended. A large-scale study is also needed to describe the extent of the problem on a national basis.