Malaria, a protozoan disease, led to numerous deaths and several new million cases raised due to the development of resistance as per the WHO malaria report 2019. This can be overcome by the development of an effective targeted plant-based delivery system through phytosomes that are effective in permeation and bioavailability to treat infected RBCs (parasitic cells). This review article explained the development of targeted Nanophytosomes to overcome resistance, to improve efficacy. This review paper also emphasized various quality-driven developmental approaches in developing an antimalarial product at a reasonable cost. By implementing molecular modeling techniques in development, a significant phytoconstituent with the capability of acting at the target (receptor or enzymes) of the parasite and the one with the capability to overcome drug resistance against resistant strains of parasites can be identified. Absorption Distribution Metabolism Excretion and Toxicity (ADMET) studies information provide a route to the design and formulation of a potent antimalarial agent. Efficient, targeted Nanophytosomal formulations can be formulated by functionalizing or conjugating with suitable targets to direct the phytoconstituent to the infected RBCs thereby achieving complete parasitic eradication. Artificial Neural Network technology (ANN), Quality by Design (QbD), molecular dynamics, and simulation studies implementation improves quality and reduces the cost of the product, as these malarial products are much utilized in low-income countries. Hence it can be concluded that targeted developmental quality-driven approaches implementation is essential for effective malarial treatment.