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The Mnisi community, an agro pastoral area adjacent to the Kruger National Park, Mpumalanga Province, South Africa, is classified as one of South Africa's 14 rural poverty nodes. It is nestled at the cusp of a human-livestock-wildlife interface. In this area, undifferentiated non-malarial acute febrile illness (AFI) is among the most common presenting sign in patients seeking healthcare at the community clinics. Recent research suggested that zoonotic pathogens either rodent-borne or tick-borne may be common aetiologies of febrile illness in the community. The study had shown that patients presenting with non-malarial AFI had prior exposure to Bartonella spp., spotted fever group Rickettsia, Coxiella burnetti and Leptospira spp. Low levels of West Nile and Sindbis, but no Rift Valley fever virus exposure were found. In a separate study, partial 16S rRNA gene sequences closely related to the zoonotic tick-borne rickettsial pathogen Anaplasma phagocytophilum have been detected in domestic dogs in the area and R. africae was found in ticks collected from dogs. Research in the area has also found rodents to be common and abundant with 76% of households reporting that they have seen rodents around their homes; of which 62% saw them on a daily basis. The active surveillance for potential pathogens in febrile patients, wild rodents, domestic dogs and cattle is thus of utmost importance in order to identify emerging zoonotic pathogens which could impact human health and livestock production in the Mnisi area and beyond.