Undoubtedly, entrepreneurial knowledge is a prerequisite for the survival of every business organization. To this, the contribution of Small and Medium Enterprises (SMEs) in the socio-economic development in most developing economies cannot be underestimated. Both developed and developing countries are living testimonies of their contributions to their nation’s growth and development. However, extant literature shows that as competition and innovation intensify in the global business market, many SMEs in developing countries are constrained by external forces that hinder the sustainability of these businesses. Hence, this paper aims to find out the mitigating factors warranting SMEs’ sustainability from the viewpoint of entrepreneurs and business owners, particularly in the manufacturing sector of Ghana, a Sub-Saharan Africa region. To achieved this objective, the study deployed a simple random sampling technique with 370 valid responses through a structured questionnaire for the analysis. Relying on PLS-SEM (partial least square and structural modeling) with the aid of ADANCO 2.2.1 software version revealed that factors such as financial challenges, technology; market penetration & acceptability; and research & development are barriers facing SMEs sustainability in the Ghanaian manufacturing sector. This study would be beneficial to entrepreneurs and business owners of SMEs in most developing countries and provide deeper insight into the SME literature at large. This study would further strengthen SME entrepreneurs and business owners to fully devise strategies that can help them to override such migrating challenges and equipped them to effectively stay competitive in the long term for the firm’s growth and survival. The limitation and future research directions are equally presented in the paper.