Malaria infection has been a very serious public health problem in Nigeria and most parts of Africa. Development of antimalarial treatments capable of providing a permanent cure for malaria has been a herculean task for drug researchers. A trial of a novel, proprietary blend formulation (Triantimal TM) in gel caps for children (n = 112) and water-soluble, 18.51 nm diameter, Nu-traNanoSphere TM encapsulated Triantimal TM drops for babies (19.9 Months ± 8.7 SD, n = 15) was conducted in Osogbo, Nigeria. The enrolled subjects were screened for malaria, treated with Triantimal TM for 16 consecutive days and sera collected on days 0, 5, 10, 16, 30, 60, and 730. Also, 31 of the children donated buffy coat samples for the gene expression studies when sera were collected. The children showed 90.2% parasite-free at 60 days and 85.1% at 730 days. The babies revealed 93.3% parasite-free at 60 days. These data show for the first time a real possibility for a cure of malaria in Nigeria. The one-time, low dose, extended treatment and synergism of the natural components minimize the ability of the parasites to develop resistance, while boosting the immune system. Indeed, the DNA amplification data showed that all aspects of the humoral, innate, and innate defensin immunity are involved in the long-term immunity against P. falciparum in which may be termed a type of "in vivo immunization".