Water resources management in estuarine environments for water supply and environmental protection typically requires estimates of salinity for various flow and operational conditions. This study develops and applies two novel deep learning (DL) models, a residual long short-term memory (Res-LSTM) network, and a residual gated recurrent unit (Res-GRU) model, in estimating the spatial and temporal variations of salinity. Four other machine learning (ML) models, previously developed and reported, consisting of multi-layer perceptron (MLP), residual network (ResNet), LSTM, and GRU are utilized as the baseline models to benchmark the performance of the two novel models. All six models are applied at 23 study locations in the Sacramento–San Joaquin Delta (Delta), the hub of California’s water supply system. Model input features include observed or calculated tidal stage (water level), flow and salinity at model upstream boundaries, salinity control gate operations, crop consumptive use, and pumping for the period of 2001–2019. Meanwhile, field observations of salinity at the study locations during the same period are also utilized for the development of the predictive use of the models. Results indicate that the proposed DL models generally outperform the baseline models in simulating and predicting salinity on both daily and hourly scales at the study locations. The absolute bias is generally less than 5%. The correlation coefficients and Nash–Sutcliffe efficiency values are close to 1. Particularly, Res-LSTM has slightly superior performance over Res-GRU. Moreover, the study investigates the overfitting issues of both the DL and baseline models. The investigation indicates that overfitting is not notable. Finally, the study compares the performance of Res-LSTM against that of an operational process-based salinity model. It is shown Res-LSTM outperforms the process-based model consistently across all study locations. Overall, the study demonstrates the feasibility of DL-based models in supplementing the existing operational models in providing accurate and real-time estimates of salinity to inform water management decision making.