Small and Medium Enterprises (SMEs) face significant challenges in managing chemical safety, often due to limited resources, inadequate infrastructure, and a lack of awareness about regulatory requirements. As chemical safety becomes increasingly critical for protecting workers, communities, and the environment, it is essential to develop tailored safety protocols for SMEs that address their unique needs. This review presents a comprehensive guide on advancing chemical safety protocols in SMEs, focusing on risk assessment, proper storage and handling of chemicals, personal protective equipment (PPE), spill prevention, and waste management. The integration of modern technologies, such as digital risk management tools, Internet of Things (IoT) sensors, and AI-driven predictive analytics, offers SMEs cost-effective solutions to enhance chemical safety. These technologies enable real-time monitoring, early warning systems for chemical hazards, and the automation of safety audits, which can significantly reduce risks and improve compliance. Additionally, fostering a strong chemical safety culture within SMEs is vital, requiring leadership commitment, employee training, and effective hazard reporting systems. Navigating regulatory frameworks and achieving compliance with limited resources presents another key challenge for SMEs. This guide highlights practical strategies for meeting safety standards, including leveraging external resources and simplifying documentation processes. Case studies showcase successful implementations of safety protocols and technologies in various SME sectors, providing insights into best practices and lessons learned. As technological advancements continue to evolve, SMEs must stay ahead by adopting innovations such as robotics, wearable safety technologies, and digital twins for chemical safety planning. This review emphasizes that a holistic approach—combining technology, policy, and workplace culture is essential for advancing chemical safety in SMEs, ensuring long-term sustainability, and safeguarding the health and well-being of workers.