A lack of surveillance and diagnostics for zoonotic diseases in rural human clinics limits clinical awareness of these diseases. We assessed the prevalence of nine zoonotic pathogens in a pastoral, low-income, HIV-endemic community bordering wildlife reserves in South Africa. Two groups of participants were included: malaria-negative acute febrile illness (AFI) patients, called febrilers, at three clinics (n = 74) and second, farmers, herders, and veterinary staff found at five government cattle dip-tanks, called dip-tanksters (n = 64). Blood samples were tested using one PCR (Bartonella spp.) and eight antibody-ELISAs, and questionnaires were conducted to assess risk factors. Seventy-seven percent of febrilers and 98% of dip-tanksters had at least one positive test. Bartonella spp. (PCR 9.5%), spotted fever group (SFG) Rickettsia spp. (IgM 24.1%), Coxiella burnetii. (IgM 2.3%), and Leptospira spp. (IgM 6.8%) were present in febrilers and could have been the cause of their fever. Dip-tanksters and febrilers had evidence of past infection to Rickettsia spp. (IgG 92.2% and 63.4%, respectively) and C. burnetii (IgG 60.9% and 37.8%, respectively). No Brucella infection or current Bartonella infection was found in the dip-tanksters, although they had higher levels of recent exposure to Leptospira spp. (IgM 21.9%) compared to the febrilers. Low levels of West Nile and Sindbis, and no Rift Valley fever virus exposure were found in either groups. The only risk factor found to be significant was attending dip-tanks in febrilers for Q fever (p = 0.007). Amoxicillin is the local standard treatment for AFI, but would not be effective for Bartonella spp. infections, SFG rickettsiosis, Q fever infections, or the viral infections. There is a need to revise AFI treatment algorithms, educate medical and veterinary staff about these pathogens, especially SFG rickettsiosis and Q fever, support disease surveillance systems, and inform the population about reducing tick and surface water contact.