Background Azithromycin is a therapeutically” relevant macrolide antibiotic registered on the Essential Medicines List of the World Health Organization. The fact that medicine is selected as an essential drug doesn’t mean that it is of good quality. Hence, a continuous quality evaluation of the drug should be mandated to verify that the right medication is available on the market. Objective To evaluate the quality of Azithromycin Tablets commonly marketed in Adama, and Modjo town, Oromia Regional State, Ethiopia. Methods All six brands were subjected to in-vitro quality control tests, which were carried out according to procedures described in the manufacturer’s method, the United States Pharmacopeia, and the WHO inspection tool. All quality control parameters were compared by one-way ANOVA. Statistically, significant difference was considered when P<0.05. The in-vitro dissolution profiles of the brands were also compared statistically using the post-hoc Dunnett test, model-independent and model-dependent approaches. Results All of the evaluated brands agreed with WHO visual inspection criteria. All of the tablets achieved the thickness, and diameter test requirements of the manufacturer’s specification (±5%). All brands passed the hardness, friability, weight variation, disintegration, identity, and assay tests as stipulated by USP. The dissolution rate was more than 80% in 30 minutes, which was within the USP specification. The model-independent parameters have confirmed that only two brands (2/6) were deemed better brands for interchangeability. Weibull and Korsemeyer’s Peppas model were the best release models. Conclusion All of the evaluated brands passed the quality specification. The model dependent approaches revealed that drug release data fit well to the Weibull, and Korsemeyer’s Peppas release models. However, the model-independent parameters have confirmed that only two brands were deemed better brands (2/6) for interchangeability. Due to the dynamic nature of low-quality medications, the Ethiopian Food, and Drug Authority should keep an eye on marketed products to guarantee their quality, especially for drugs like azithromycin for which non-bioequivalence data from the study has revealed a clinical concern.