Human African trypanosomiasis (HAT) is prevalent in African countries, covering 37 countries, mostly sub-Saharan. A limited number of drugs are available to cure this neglected disease. In the present work, quantitative structure–activity (toxicity) relationships (QSA(T)R) analysis has been performed for a dataset of 54 6-arylpyrazine-2-carboxamides as Trypanosoma brucei inhibitors to identify the important structural features required for future optimization of lead candidates. The QSA(T)R models satisfy OECD guidelines and have high statistical robustness. The QSA(T)R models are based on easily interpretable molecular descriptors. The QSA(T)R models indicate that Trypanosoma brucei inhibitory activity of 6-arylpyrazine-2-carboxamides has correlation with the presence of N-sec-butylformamide and substituted benzene. The results could be beneficial for further optimization of 6-arylpyrazine-2-carboxamides as Trypanosoma brucei inhibitors. Some potential candidate molecules have been proposed.