Malaria is an enormous threat to public health due to the emergence of Plasmodium falciparum resistance to widely used anti-malarials, such as chloroquine. Additionally, the commercially used antimalarial drugs affected by this drug resistance are associated with side effects; thus, there is a need to identify a template with fewer side effects and improved efficacy. Therefore, in the present study, a click chemistry approach was used to design and synthesize glycyrrhetinic acid-triazole derivatives and determine their antiplasmodial activity against a chloroquine-sensitive (NF-54) strain of P. falciparum. Among the sixteen glycyrrhetinic acid derivatives, compound-17 was found to be the most active against the chloroquine-sensitive (NF-54) strain of P. falciparum with an IC50 of 0.47 ± 0.04 μM. However, compound-17 showed no effect on heme polymerization, the most common target in malaria parasites. The increased ROS levels, decrease in the GSH/GSSG ratio, metabolic activity, mitochondrial potential, further increase in the caspase-3 activity, and DNA damage are possibly responsible for the apoptotic death of P. falciparum. Interestingly, compound-17 showed significant chemo-suppression of parasitemia and hemoglobin content, reduced hepatic damage, decreased production of inflammatory cytokines, and decreased plasmodial infection in mice models. In vitro cytotoxicity/hemolysis assay suggests that compound-17 is safe to explore its therapeutic properties further. Based on these results, the synthesized compound-17 appears to be a viable template derivative, able to overcome the problem of drug-resistance and enhance anti-plasmodial activity against P. falciparum, making it an attractive anti-malarial agent.