Three major forms of hunting are believed to be on the increase in the Western Cape Province of South Africa, posing independently and synergistically some of the greatest threats to the continued survival of local wildlife. Firstly, there is growing evidence of the presence and reliance of local communities on bushmeat harvesting by means of wire-snare poaching, potentially implying severe reductions or extirpations of target species, high rates of non-target off-take, and the loss of entire communities. Secondly, human-wildlife conflict poses a threat to the livelihoods and agricultural security of many stakeholders living at the interface of human development and natural habitat in the Boland, resulting in the vast eradication of damage-causing animals (DCA’s). Finally, the use of animals and animal-derived materials in traditional medicine constitutes an important part of the belief-systems of indigenous African cultures, and is believed to be rapidly expanding. Due to the severity of the consequences reported elsewhere globally, and the general lack of local information with which to quantify the extent and impact of these hunting practices locally, structured interviews were conducted with farmers (n = 103) and labourers (n = 307) on private agricultural properties bordering protected areas (PA’s). In addition, semi-structured interviews were conducted with traditional healers (n = 36) operating from impoverished, rural communities near PA’s. Our reliance on the knowledge and experiences of local people elucidated several dynamic and interwoven social, economic and ecological factors underlying wildlife off-take, and subsequently allowed for the quantification, documentation and mapping of vertebrate off-take at the human-wildlife interface. Wire-snare poaching incidence and behaviour was strongly influenced by economic factors relating to poverty, a lack of governing regulations and punitive measures, interpersonal development, and abiotic factors such as proximity to major residential areas, roadways and PA’s. Results showed that local, male farmers managing large commercial properties affiliated with regional conservancies were most likely to rely on the lethal control of DCA’s. The highest level of tolerance by farmers was shown for primates and ungulates, while tolerance for carnivores, avifauna and invasive or feral species was comparatively lower. The spatial location of observed and expected zones of species-specific risk on a regional level was also mapped using a maximum entropy algorithm. We recorded 26 broad use-categories for 12 types of animal parts or products from 71 species used in traditional medicine. The most commonly sold items were skin pieces, oil or fat, and bones. To conclude, we conducted a synergistic assessment of species’ vulnerability to the combined impacts of the above-mentioned hunting practices, and subsequently found that leopard, grey duiker, chacma baboon, caracal, Cape porcupine, aardvark, genet spp., and cape clawless otters experience the highest potential endangerment. This study provided the first demonstration of the multifaceted and complex nature of hunting practices in the Boland Region, opening a dialogue between local communities and conservation agencies. The primary goals being to broaden our understanding of the heterogeneity in local-scale socio-ecological dynamics, to apply policies for effective management and eradication, to prioritize areas and species for intervention, to provide for more accurate allocation of conservation resources, and to provide grounds for future research in the area and elsewhere.