Plastic pollution poses significant environmental, economic, and health risks to waterways globally, including Ghana. The paper examines the legislative responses to plastic pollution in Ghana's rivers, lakes, and coastal areas, focusing on enhancing policy interventions across Africa and other regions with similar challenges. The paper further analyzes key legislative instruments and regulatory frameworks in terms of their evolution and effectiveness in sustainably addressing plastic waste pollution in Ghana, offering insights into how these approaches can be scaled regionally or globally. International and regional treaties such as the Stockholm Convention on Persistent Organic Pollutants, the Basel Convention on the Control of Transboundary Movements of Hazardous Wastes and their Disposal, and the Bamako Convention on the Ban of the Import into Africa and the Control of Transboundary Movement and Management of Hazardous Wastes within Africa have influenced the legislative and regulatory landscape in Ghana. The prevailing national laws, including the Environmental Protection Agency Act of 1994, the Hazardous and Electronic Waste Control and Management Act of 2016, and the National Plastic Management Policy are examined to determine their level of compliance with the international and regional mechanisms. The major challenges - normative and institutional - in implementing and enforcing these laws are identified. The study advances strategic reforms for enhancing the legal and institutional framework for addressing plastic pollution and protecting waterways. It argues for the adoption of comprehensive and precise legislation, effective enforcement mechanisms, and improved waste management infrastructure, with lessons applicable to both regional and international environmental governance.