Human African trypanosomiasis (HAT), a fatal infection caused by Trypanosoma brucei (T. brucei) is considered as a neglected disease in the tropical areas, and newer agents with unique mechanism of action are urgently needed. In this work, 65 Imidazopyridine analogues from known literature were selected for building statistically robust genetic algorithm (GA) based QSAR models. Furthermore, values for the various cross-validation properties supported its statistical robustness (model 1, [Formula: see text], RMSE[Formula: see text], MAE[Formula: see text], CCC[Formula: see text], and [Formula: see text]). Our in silico ADMET analysis revealed that a designed molecule, S10 may act as potent lead (T. brucei, pEC[Formula: see text] ([Formula: see text]M), [Formula: see text]) with better pharmacokinetics, no carcinogenicity, class III acute oral toxicity, minimal OCT1 and OCT2 inhibitions and no eye corrosion profiles. Our molecular docking analysis (on 42 drug targets) for a dataset and designed molecules demonstrated higher binding affinity of Imidazopyridine analogues with T. brucei farnesyl diphosphate synthase (TbFPPS) (PDB id: 2I19). This observation was further supported by 100[Formula: see text]ns molecular dynamics analysis retaining better stability of complex. Thus, imidazopyridine analogues would provide a promising scaffold for the development of anti-HAT agents.