Effectively simulating the variation in suspended sediment concentration (SSC) in estuaries during typhoons is significant for the water quality and ecological conditions of estuarine shoal wetlands and their adjacent coastal waters. During typhoons, SSC undergoes large variations due to the significant changes in meteorological and hydrological factors such as waves, wind speed, and precipitation, which increases the difficulty in simulating SSC. Therefore, in this study, we use an optimized Principal Component Analysis Long Short-Term Memory (PCA-LSTM) framework with an attention mechanism to simulate the SSC in the Yangtze Estuary during Typhoon In-Fa. First, we integrate data from different sources into a multi-source dataset. Second, we use the PCA to reduce the dimensionality of the multi-source data and eliminate redundant variables in the feature data. Third, we introduce an attention mechanism to optimize the long and short-term memory (LSTM) model. Finally, we use the differential evolution (DE) algorithm for hyperparameter selection and merge the feature data with the SSC data as the input of the optimized LSTM network to simulate SSC. The results showed that SSC’s fitting coefficients (R2) at four hydrological stations improved by 7.5%, 6.1%, 7.4%, and 7.8%, respectively, using the attention-based PCA-LSTM compared to the PCA-LSTM. Moreover, compared to the traditional LSTM model, the R2 was improved by 33.8%, 30.5%, 32.0%, and 28.6%, respectively, using the attention-based PCA-LSTM framework. The study indicates that the selection of input variables can affect the model results. Introducing an attention mechanism can effectively optimize the PCA-LSTM framework and improve the simulation accuracy, which helps simulate the non-linear process of SSC variation occurring during Typhoon In-Fa.