Background: Drug therapy remains the principal management strategy for malaria but is increasingly challenged by the emergence of drug-resistant malaria parasites. The need for new antimalarial drugs is urgent, yet drug discovery and development are hindered by high costs, long durations, and safety concerns that prevent approval. The current study aimed to determine antiplasmodial activities of approved drugs in combination with artemether (ART) and lumefantrine (LU). Methods: Using the SYBR Green I assay test, this study investigated the efficacy of epirubicin (EPI) and pelitinib (PEL) combined with ART and LU at fixed drug–drug ratios (4:1, 3:1, 1:1, 1:2, 1:3 and 1:4) and volume/volume. These combinations, as well as single drug treatments, were tested against cultured strains of Plasmodium falciparum (W2, DD2, D6, 3D7 and F32-ART) and fresh and cultured clinical isolates. The fifty percent inhibition concentration (IC₅₀) and a mean sum of fifty percent fractional inhibition concentration (FIC₅₀) were determined. Results: Synergism was observed when EPI was combined with both ART and LU across all fixed ratios with a mean of mean FIC₅₀ values of 1) when tested against strains of P. falciparum and clinical isolates. Conclusions: This study underscores the utility of alternative drug discovery and development strategies to bypass cost, time, and safety barriers, thereby enriching the antimalarial drug pipeline and accelerating the transition from lab to market.