The World Health Organization documented 247 million reported malaria cases worldwide resulting in 619,000 fatalities in 2021. More than 70% of these deaths are attributed to Children under five years of age and sub-Saharan Africa is the region in which the highest number of deaths occur. The Plasmodium falciparum parasite is the deadliest form of malaria, and treating falciparum infection is becoming more challenging due to the emergence of drug-resistant parasites, causing a decrease in the efficiency of antimalarial medications. Artemisinin combination therapy is now considered the gold standard for malaria treatment; however, this method is at risk due to parasites exhibiting delayed clearance to artemisinin and resistance to partner drugs such as lumefantrine, amodiaquine, mefloquine, piperaquine, and sulfadoxine/pyrimethamine. This review assessed drug targets in Plasmodium falciparum for the development of novel antimalarials. Over Eighty-five papers on malaria, Plasmodium falciparum protein targets, and protein inhibitors were gathered from Google Scholar, ProQuest, PubMed, and Science Direct, between 2012 and 2023. Only articles with comparable keywords on malaria drug targets concentrating on enzyme proteins, carrier molecules present in Plasmodium falciparum, and their inhibitors were retrieved for review, while articles within that range that did not provide definite data were excluded. Most recently, inhibitors of dihydroorotate dehydrogenase (DHODH), artefenomel (OZ439), and ferroquine have been reported and are being explored in combination with other partner medications to work against different stages of plasmodium parasite. In identifying target proteins for drug development, essentiality and vulnerability throughout the life cycle of the parasite, its druggability, and the availability of target-based assays are critical factors. The use of modern proteomics and cellular proteins from database search which assists in parasite proliferation delivers optimal information on the new generation of lead compounds. In addition, advances in in silico methods enable the identification of protein targets for drug development.