Major cities in transitional and developing countries are facing the ever-growing challenge of managing solid waste in a sustainable manner. While a variety of treatments exist for solid waste, cities are in need of a sustainable integrated municipal solid waste management (MSWM) system. Such a system is meant to assist them in selecting and investing in an appropriate combination of treatments for the waste they generate, depending on the composition and quantity of this waste. This study presents a systems analysis of the MSWM in Cairo. A constrained non-linear mathematical model is developed to represent an underlying model of a MSWM system, with six waste material flows (cardboard and paper, plastics, metals, glass, organic material, and others). The developed model depicts combinations of five treatment alternatives (composting, anaerobic digestion, mechanical biological treatment, incineration, and landfilling). The treatment methods and their capacity are determined by the model, indicating possible optimal design solutions and recommendations. Starting with an evaluation of the status quo of the MSWM system in Cairo, the paper proposes a staged strategy, involving investigating improvements to the current mixed-waste management system, then exploring the possibility of introducing at-source waste sorting. The environmental and economic implications of different scenarios are analyzed and compared. A material flow analysis, including input data uncertainties, is also conducted by applying substance flow analysis. This analysis shows the difference between the status quo and the proposed improved solutions for diverting waste from landfills and, thus, decreasing carbon dioxide emissions.