In many developing countries, there are certain health problems faced by the public, one among them is Malaria. This tropical disease is mainly caused by Plasmodium falciparum. It is categorized as a disaster to public health, which increases both mortality and morbidity. Numerous drugs are in practice to control this disease and their vectors. Eco-friendly control tools are required to battle against vector of this significant disease. Nanotechnology plays a major role in fighting against malaria. The present paper synthesized Zinc oxide nanoparticles (ZnO NPs) using zinc nitrate via simple green routes with the help of aqueous peel extract of Lagenaria siceraria (L. siceraria). The synthesized ZnO NPs were characterized by various biophysical methods. Moreover, the extract of L. siceraria and their mediated ZnO NPs was experimented against III instar larvae of An. stephensi. The impact of the treatment based on ZnO NPs concerning histology and morphology of mosquito larval was further observed. In the normal laboratory environment, the efficiency of predation of Poeciliareticulata (P. reticulata) against An. Stephensi larvae was found to be 44%, whereas in aqueous L. siceraria extract and its mediated ZnO NPs contaminated environment, P. reticulate showed predation efficiency of about 45.8% and 61.13% against An. Stephensi larva. L. siceraria synthesized ZnO NPs were examined against the Plasmodium falciparum CQ-sensitive strains. The L. siceraria extract and its mediated ZnO NPs showed the cytotoxic effects against HeLa cell lines with an IC50 value of 62.5 µg/mL. This study concludes that L. siceraria peel extract and L. siceraria synthesized ZnO NPs represent a valuable green option to fight against malarial vectors and parasites.