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Abstract Estuarine exchange flow controls the salt balance and regulates biogeochemistry in an estuary. The Albemarle‐Pamlico estuarine system (APES) is the largest coastal lagoon in the U.S. and historically susceptible to a series of environmental issues including salt water intrusion and eutrophication, yet its estuarine exchange flow is poorly understood. Here, we investigate the estuarine exchange flow in the APES, its tributary estuaries (Pamlico and Neuse), and sub‐basin Albemarle Sound using the total exchange flow analysis framework based on results from a deterministic numerical model. We find the following: (a) Dynamics controlling estuarine exchange flow in the APES vary spatially and depend on timescales considered. At inlets, estuarine exchange flows respond to both tidal prism and residual water levels at weather‐to‐spring/neap timescales. At a long quasi‐steady timescale represented as annual means, estuarine exchange flow is dominated by barotropic flow. Within the tributary estuaries, estuarine exchange flows at timescales of wind periods are controlled by wind‐induced straining, whereas the quasi‐steady state condition is dominated by gravitational circulation. At Albemarle Sound, exchange flow is dominated by the residual water levels at weather‐to‐spring/neap timescales, while at quasi‐steady state it is controlled by barotropic flow. (b) At the quasi‐steady annual timescale, the salt content decreases with river discharge. At the weather‐to‐spring/neap timescales, salt content is insensitive to variations in estuarine exchange flow, except for within Albemarle Sound. (c) Estuarine exchange flow likely influences the biogeochemistry of the APES by playing a key role in regulating the flushing efficiency and material exchange, a role that has been previously overlooked.