Sewage leakage, including uncollected, collected but exfiltrated, and collected but discharged with stormwater in combined sewer overflows, becomes a key challenge to clean water around the world. This study proposed a mass balance model to quantify sewage leakage and analyzed its influencing factors. Approximately 56% (53%–59%) of domestic total nitrogen loads in the Yangtze River basin of China leak out without treatment, two-thirds are exfiltrated or overflowed, significantly impacting receiving water quality. Cities with higher precipitation have greater leakage, indicating overflows are important. Pipe density has limited impact, showing higher importance of pipe quality over quantity. The per capita leakage rate first increases with city size and then decreases, showing the economies of scale. Yet uneven distribution of population and economy within megacities leads to greater leakage. Hence, separated sewage systems of rainwater and wastewater, regular maintenance and adapting centralized and decentralized systems are recommended, tailored to city-specific leakage characteristics.