The study investigated socio-cultural characteristics of pastoralists that influenced on the tsetse-trypanosome-cattle reservoir interface thereby predisposing them to HAT in Niger State, North-central Nigeria. It was a cross-sectional survey of adult pastoral herders, aged 30 years and above, and conducted between October 2012 and February 2013. A face-to-face structured questionnaire was administered on the pastoralists nested in 96 cattle herds with questions focused on pastoralists’ socio-cultural activities and behavioral practices related to HAT risk. Descriptive and analytic statistics were used to describe the obtained data. A total of 384 pastoralists participated, with mean age of 49.6 Â ± 10.76 SD years. Male respondents constituted 86.7% of gender, while pastoralists of age group 40–49 years constituted 35.4% of respondents. About 59.4% of the pastoralists had knowledge about HAT and its symptoms and only 33.9% of them believed that cattle served as reservoir of HAT trypanosome. Knowledge/belief levels of the pastoralists about African trypanosomiasis occurrence in humans and animals were statistically significant. Males were four times more likely to be exposed to HAT (OR = 3.67; 95% CI: 1.42, 9.52); age group 60–69 was also four times more likely to be exposed (OR = 3.59; 95% CI: 1.56, 8.28); and nomadic pastoralists were two times more likely to be exposed to HAT (OR = 2.07; 95% CI: 1.37, 3.14). All cultural practices significantly influenced exposure to HAT with extensive husbandry system three times more likely to predisposed pastoralists to HAT (OR = 3.21; 95% CI: 1.65, 6.24). Socio-cultural characteristics of pastoralists influenced exposure to HAT risk and, therefore, there is a need to sensitize them to bring changes to their socio-cultural practices and perceptions to achieve effective and long term sustainable HAT control. Elimination strategies of parasites in animals and vectors should be considered to avoid reintroduction from animal reservoirs.