Context: Malarial remains a leading course of death in developing countries. Current treatment protocol involves the use of artemisinin-based combination therapy. In endemic areas, cost of treatment is a concern hence generic prescription is on the high. It is therefore necessary to investigate how equivalent or otherwise the generics are to the innovator brand Coatem®. Aims: To compare the physicochemical properties and in vivo bioavailability of a locally manufactured generic artemether-lumefantrine tablet formulation and that of the innovator brand sold on the Kumasi market, Ghana. Methods: The most used locally manufactured generic and the innovator brands were sampled from retail pharmacies. The samples were confirmed by colorimetry. Pharmaceutical equivalence of the brands was determined using compendial tests. In vivo bioavailability study on the two brands was done using a two-period, single dose, cross-over design involving 20 healthy rabbits. Pharmacokinetic parameters (AUC0-72, AUC0-∞, and Cmax) for both brands derived from the study were analysed statistically. Results: Both the generic and innovator brands passed the physicochemical tests. The artemether component of both brands complied with the pharmacopoeia specification for dissolution testing while the lumefantrine did not. Average bioequivalence was demonstrated per the FDA criterion with the geometric mean ratios and corresponding 90% confidence intervals falling within the acceptable limits of 0.80 – 1.25. Conclusions: Based on the similarity demonstrated between the two brands, evidence have been shown to support substitutability of the often-expensive innovator brand with the affordable locally produced brand.