Background <p>Snakes are a group of vertebrates that evoke strong feelings and generate much interest. Southern African pythons (<i>Python natalensis</i>) are the largest snake species in southern Africa, providing substantial ecosystem services, but also negatively impacting people by consuming their livestock and pets. Our study aimed to assess the attitudes of South Africans towards southern African pythons, and to analyse what might influence either a positive or a negative attitude towards them. This is important because of the significant persecution this species is facing, as well as its declining population trend.</p> Methods <p>In 2023, 2024, and early 2025, we employed a mixed-model approach that combined face-to-face interviews to complete the questionnaire, and an electronic online version that could be completed by respondents, to investigate the perceptions and attitudes of people towards pythons in South Africa, particularly in KwaZulu-Natal Province. This resulted in 438 responses from diverse demographic and geographic backgrounds, which we then analysed to better understand how South Africans view these snakes.</p> Results <p>The results were not as predicted, with a significant majority having an overall positive attitude towards these snakes. Valuable insights into the cultural significance of pythons and how this trend is evolving over time were obtained, as well as some insight into the misinformation surrounding this species and the factors that influence these perceptions. We also assessed superstitions involving pythons, as well as traditional medicine (<i>muthi</i>) uses, and how people perceived pythons to be dangerous.</p> Conclusions <p>While the general attitude towards pythons appeared to be positive, there was a concerning element of misinformation as well as persecution, and we suggest that efforts be made to educate and inform people wherever possible.</p>