Food-borne disease outbreaks are common and offer valuable insights into the causes, impacts, and mechanisms underlying food pathogens. This also serves as a good foundation to validate the performance of current best practice control methods, for example antibiotics, that are used in the fight against food pathogens. Listeriosis outbreaks, caused by Listeria monocytogenes , is no exception. In 2018, South Africa experienced the largest global listeriosis outbreak recorded to date. However, despite the scale of this outbreak, information on the bacterium and its resistance towards antibiotics is still severely lacking. Furthermore, until now it remained to be determined whether L. monocytogenes antibiotic resistance patterns in South Africa mirror resistance patterns elsewhere in the world. The aim of this study was therefore to evaluate the efficacy of antibiotics that are currently used against L. monocytogenes . Using the European Committee on Antimicrobial Susceptibility Testing (EUCAST) disc diffusion method, L. monocytogenes isolates (n = 177) from diverse origins in the Western Cape, South Africa (clinical, food, and environment) were tested for susceptibility against five different antibiotics, namely ampicillin, erythromycin, chloramphenicol, gentamicin, and tetracycline. Isolates were collected over a period of two years (2017–2019). All isolates were susceptible to ampicillin, the currently recommended antibiotic, while a large number of isolates were resistant to chloramphenicol, erythromycin, and tetracycline. Also, patterns of resistance observed here are different to patterns observed elsewhere. The findings of this study demonstrate that it is imperative to continuously monitor the efficacy of currently recommended antibiotics, since resistance patterns can quickly develop when such antibiotics are overutilized, and secondly, that it is crucial to assess local antibiotic resistance patterns in conjunction with global patterns, since the latter is not necessarily generalizable to local scales.