The presence of zoonotic diseases adversely affects livestock production and farmers' livelihood in communal areas. A lack of awareness about zoonotic diseases among rural farmers results in economic losses and health risks. The far north-eastern corner of KwaZulu-Natal (KZN) province, South Africa, is home to large numbers of communal livestock farmers who live adjacent to wildlife reserves and international borders. There have been reports of zoonotic and trade-sensitive diseases in the area, but farmers' knowledge, attitudes, and practices (KAP) in this regard are poorly understood. This study investigated the KAPs of communal livestock farmers in far northern KZN regarding livestock and zoonotic diseases found in the livestock–wildlife interface and determined the constraints and challenges faced by communal livestock farmers. A cross-sectional questionnaire survey was conducted among 504 livestock farmers at 45 dip tanks between August and November 2020, using a closed-ended questionnaire. Although the overall level of knowledge regarding animal disease transmission was fairly good (score: 53.2%), 25.4% and 21.4% of farmers had moderate and poor knowledge, respectively, about zoonotic disease transmission and prevention. Over 40% of the farmers were not aware of the zoonotic nature of wildlife and livestock diseases. Older farmers, despite their lower level of education, were more knowledgeable on animal diseases and had better practices in regard to zoonotic disease prevention and management compared to younger ones. The majority of farmers cited the lack of water, insufficient grazing land, stock theft, the restriction of animal movement, and animal diseases as the most significant challenges they faced regarding animal production. The results indicate the need for extension programs that target educating livestock farmers to improve their knowledge of these diseases.