The Oujiang River Estuary (ORE) is a macrotidal estuary in southeast Zhejiang Province of China. Although the economy has developed rapidly over the past two decades, few studies have been explored on the estuarine dynamics. Based on in situ measurements, we established a 3-D numerical model to investigate salt intrusion and its response to river discharge, tide, and the salinity at river mouth. We obtained following conclusions. (1) Although salt intrusion length followed a power law with respect to overall river discharge span capturing the fundamental trend, salt intrusion length should be analysed at different ranges of river runoff, as regression accuracy increased substantially at individual range. (2) Estuarine salt transport was dominated by two components of downstream Euler flux and upstream Stokes flux, while tidal shear effects and tidal pumping contributed less. (3) Salt intrusion length not only was a function of river runoff and tidal range but also influenced, with more indicating significance, by mouth salinity. Additionally, geometry effect and nonlinearity might amplify the strong dependences of salt intrusion on mouth salinity and tidal range. (4) Results from partial least squares revealed an approximately linear relation between salt intrusion length and the determining factors of tidal range, river runoff, and river mouth salinity. The hysteretic term was found to have most important influence on salt intrusion length. The response time of salt intrusion in ORE varied with runoff from ~ 2.5 days for medium discharge to ~ 1 day for large and small discharges.