Abstract Malaria drug resistance presents a significant challenge to malaria control and elimination efforts. Therefore, it is crucial to conduct regular surveillance to assess the therapeutic efficacy of first-line antimalarial drugs, which informs policy decisions to manage this threat. This study aimed to evaluate the therapeutic efficacy of artemether-lumefantrine (AL), which is the first-line treatment for uncomplicated malaria in Ethiopia since 2004, for uncomplicated Plasmodium falciparum malaria in Metehara, central-east Ethiopia. Using a one-arm prospective evaluation design, the study assessed the clinical and parasitological responses of patients with uncomplicated P. falciparum malaria. Initially, 80 patients (50 males and 30 females) were screened, and a total of 73 participants (44 males, 29 females) successfully completed the follow-up. The results indicated rapid parasite clearance and resolution of clinical symptoms, with all patients achieving complete recovery from asexual parasitemia and fever by day 3. The prevalence of gametocytes decreased from 6.3% on day zero to 2.5% on days two, three, seven, and ultimately achieving complete clearance afterwards. The overall cure rate for AL treatment, without a polymerase chain reaction correction, was 100%, demonstrating its high efficacy in effectively eliminating the malaria parasite in patients. Importantly, no serious adverse events related to AL treatment were reported during the study, suggesting its safety and tolerability among the participants. These findings confirm that, even 20 years after its introduction in Ethiopia, AL remains an effective treatment for uncomplicated P. falciparum malaria in the study site.