Accurate prediction of estuarine salinity can effectively mitigate the adverse effects of saltwater intrusion and help ensure the safety of water resources in estuarine regions. Presently, diverse data-driven models, mainly neural network models, have been employed to predict tidal estuarine salinity and obtained considerable achievements. Due to the nonlinear and nonstationary features of estuarine salinity sequences, this paper proposed a multi-factor salinity prediction model using an enhanced Long Short-Term Memory (LSTM) network. To improve prediction accuracy, input variables of the model were determined through Grey Relational Analysis (GRA) combined with estuarine dynamic analysis, and hyperparameters for the LSTM model were optimized using a multi-strategy Improved Sparrow Search Algorithm (ISSA). The proposed ISSA-LSTM model was applied to predict salinity at the Cangqian and Qibao stations in the Qiantang Estuary of China, based on measured data from 2011–2012. The model performance is evaluated by mean absolute error (MAE), mean absolute percentage error (MAPE), root mean square error (RMSE), and Nash-Sutcliffe efficiency (NSE). The results show that compared to other models including Back Propagation neural network (BP), Gate Recurrent Unit (GRU), and LSTM model, the new model has smaller errors and higher prediction accuracy, with NSE improved by 8–32% and other metrics (MAP, MAPE, RMSE) improved by 15–67%. Meanwhile, compared with LSTM optimized with the original SSA (SSA-LSTM), MAE, MAPE, and RMSE values of the new model decreased by 13–16%, 15–16%, and 11–13%, and NSE value increased by 5–6%, indicating that the ISSA has a better hyperparameter optimization ability than the original SSA. Thus, the model provides a practical solution for the rapid and precise prediction of estuarine salinity.