Background: Plasmodium species are obligate intracellular protozoan parasites that cause malaria, which is a major public health problem. One of the most important malaria control strategies in endemic areas is the treatment of uncomplicated Plasmodium falciparum infections with artemether-lumefantrine plus a single low-dose primaquine. However, drug resistance to uncomplicated Plasmodium falciparum infection remains a threat to effective malaria control programs worldwide. Furthermore, the periodic assessments of the efficacy of artemether-lumefantrine plus single low-dose primaquine for the treatment of uncomplicated Plasmodium falciparum malaria and its adverse effects are poorly addressed in Ethiopia. Objective: This study aimed to assess the therapeutic efficacy and safety of artemether-lumefantrine plus a single low-dose primaquine for the treatment of uncomplicated Plasmodium falciparum malaria. Methods: An in vivo prospective single-arm study was conducted at Maksegnit Health Center from February to May 2022. Eighty-eight uncomplicated Plasmodium falciparum malaria cases whose age ≥18 years were enrolled in the study. A standard dose of artemether-lumefantrine twice daily for three days along with a single low-dose primaquine (0.25 mg/kg) was given, and clinical and parasitological outcomes were assessed for 42 days. Capillary blood was collected for parasitological identification, quantification, genotyping, and hemoglobin determination. Thick and thin blood films were prepared, stained with Giemsa, and examined microscopically. The nested polymerase chain reaction method was used to detect and genotype recurrent Plasmodium falciparum cases. Hemoglobin level was measured by the HemoCue HB 301 Sweden spectrophotometer on days 0, 14, 28, and 42. Data entry and analysis were performed using the World Health Organization-designed Excel spreadsheet and SPSS version 25 software. All comparisons were performed at a 95% CI and a significant level of <0.05. Result: Among the 88 enrolled patients, 85 patients completed a 42-day follow-up. The per-protocol polymerase chain reaction uncorrected and corrected cure rates were 94.1% (95% CI: 86.8–98.1%) and 96.4% (95% CI: 89.8–99.2%), respectively. Artemether lumefantrine plus a single low dose of primaquine cleared parasites and fevers quickly, with only one participant having parasitemia on day 3 and no febrile cases on day 2. On day three, gametocytes were completely cleared. The mean hemoglobin on days 0, 14, 28, and 42 was 14.2±2.07 g/dl, 13.96±1.47 g/dl, 14.4±1.32 g/dl, and 14.65±1.35 g/dl, respectively. There was no statistically significant difference in mean hemoglobin among the follow-up days (0, 14, 28, and 42). Generally, adverse events were mild to moderate, but no severe adverse events were recorded. Therefore, Artemether lumefantrine plus single-dose primaquine should continue as a first-line drug to treat uncomplicated Plasmodium falciparum malaria in the study area. Conclusion: Artemether-lumefantrine plus single-low-dose primaquine was efficacious and safe in the study area for the treatment of uncomplicated Plasmodium falciparum malaria. Key words: Efficacy, Adverse events, Artemether-lumefantrine, Primaquine, Plasmodium falciparum, Ethiopia