The inclusion of small and medium-sized pharmaceutical companies from developing countries in global supply chains is essential for the expansion and durability of the worldwide pharmaceutical sector. South Africa, with its rapidly growing pharmaceutical industry, is leading the way in this process of integration. It provides a distinct case study of the difficulties and advantages that small and medium-sized enterprises face in the pharmaceutical sector. This study seeks to conduct a systematic analysis of the current literature about the obstacles and possibilities encountered by small and medium-sized pharmaceutical companies in South Africa as they strive to become part of global supply chains. The objective is to offer a thorough summary of the existing research in this field. This study utilised the PRISMA systematic literature review approach to evaluate 26 peer-reviewed papers and academic publications from the Scopus database that are pertinent to pharmaceutical small and medium-sized enterprises (SMEs) in South Africa. The data were extracted using Atlas-ti, which facilitated a thematic analysis to identify and categorise the primary difficulties and opportunities faced by these firms. The assessment has found four main obstacles: regulatory impediments, budgetary limitations, operational and logistical concerns, and market rivalry. On the other hand, there were also important prospects identified, such as the possibility for expanding the market, developments in technology, initiatives to promote sustainability, and the development of collaborative networks. These findings emphasise the complex and diverse ways in which small and medium-sized enterprises (SMEs) become part of global supply chains. They illustrate the obstacles and opportunities that SMEs encounter in their efforts to succeed. Pharmaceutical small and medium-sized enterprises (SMEs) in South Africa encounter a range of intricate obstacles as they strive to integrate into the global supply chain. However, they also have multiple chances to utilise growth and gain a competitive edge. Effectively managing these difficulties and possibilities is crucial for their incorporation into worldwide markets. This study enhances the scholarly discussion on the integration of global supply chains by conducting a detailed investigation of small and medium-sized pharmaceutical companies in the context of a developing country. This study provides valuable insights into the unique problems and possibilities faced by these businesses, which can be used to guide future research and develop practical strategies to enhance global integration.