Neglected tropical diseases (NTDs) form a group of diseases that are strongly associated with poverty, flourish in impoverished environments, and thrive best in tropical areas, where they tend to present overlap. They comprise several diseases, and the symptoms vary dramatically from disease to disease, often causing from extreme pain, and untold misery that anchors populations to poverty, permanent disability, and death. They affect more than 1 billion people worldwide; mostly in poor populations living in tropical and subtropical climates. In this review, several complementary in silico approaches are presented; including identification of new therapeutic targets, novel mechanisms of activity, high-throughput screening of small-molecule libraries, as well as in silico quantitative structure–activity relationship and recent molecular docking studies. Current and active research against Sleeping Sickness, American trypanosomiasis, Leishmaniasis and Schistosomiasis infections will hopefully lead to safer, more effective, less costly and more widely available treatments against these parasitic forms of Neglected Tropical Diseases (NTDs) in the near future.