Salt intrusion presents a significant environmental challenge in numerous estuaries around the world, including the Modaomen Estuary in China. This phenomenon typically occurs during the winter season due to reduced freshwater flow. However, an unusual salt intrusion event was observed during the autumn of 2022, coinciding with a typhoon. In this study, we assess the response of the Modaomen to Typhoon Nesat in 2022 and examine the influence of the typhoon on salt intrusion using the Semi-implicit Cross-scale Hydroscience Integrated System Model (SCHISM). The model results reveal that salt intrusion during a typhoon event is primarily driven by the storm surge and landward Ekman transport. Northeasterly winds enhance stratification between saltwater and freshwater in the Modaomen. Moreover, with the typhoon’s passage, the Denglongshan Station recorded a peak salinity of 17 psu, with salt intrusion stretching 29 km further. This escalation led to salinity levels surpassing the local drinking water standard of 0.5 psu across all freshwater intake points in Zhuhai City. Numerical experiments indicate that if Typhoon Nesat had occurred during spring tides, the salt intrusion would have been less severe. Furthermore, the study revealed that regulating the upstream runoff could potentially alleviate the effects of typhoon-induced salt intrusion on ensuring a safe water supply. With a runoff increase to 4000 m3/s, the impact of typhoons on Modaomen’s drinking water supply can be managed, and at 6000 m3/s, the influence of typhoons on water supply becomes negligible.