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This paper presents a comprehensive approach to predicting short-term (for the upcoming 2 weeks) changes in estuarine dissolved oxygen concentrations via machine learning models that integrate historical water sampling, historical and upcoming 2-week meteorological data, and river discharge and discharge metrics. Dissolved oxygen is a critical indicator of ecosystem health, and this approach is implemented for the Neuse River Estuary, North Carolina, U.S.A., which has a long history of hypoxia-related habitat degradation. Through meticulous data preprocessing and feature selection, this research evaluates the predictions of dissolved oxygen concentrations by comparing a recurrent neural network with four other models, including a Multilayer Perceptron, Long Short-Term Memory, Gradient Boosting, and AutoKeras, through sensitivity experiments. The input predictors to our prediction models include water temperature, turbidity, chlorophyll-a, aggregated river discharge, and aggregated wind based on eight directions. By emphasizing the most impactful predictors, we streamlined the model-building processes and built a hindcast system from 2015 to 2019. We found that the recurrent neural network model was most effective in predicting the dissolved oxygen concentrations, with an R2 value of 0.99 at multiple stations. Different from our machine learning hindcast models that used observed upcoming meteorological and discharge data, an actual forecast system would use forecasted meteorological and discharge data. Therefore, an actual operational forecast may have lower accuracy than the hindcast, as determined by the accuracy of the predicted meteorological and discharge data. Nevertheless, our studies enhance our understanding of the factors influencing dissolved oxygen variability and set the basis for the implementation of a predictive tool for environmental monitoring and management. We also emphasized the importance of building station-specific models to improve the prediction results.