Regional, seasonal, and interannual variations of freshwater inputs, biogeochemical transformations, and pelagic-benthic interactions were examined in the Patuxent River estuary. Monthly rates of net biogeochemical production (or consumption) and physical transport of carbon, oxygen, and nutrients were calculated for 6 estuarine regions using data-constrained salt- and water-balance computations (box model) with hydrologic and water quality data. Assuming fixed stoichiometry for O2, carbon, and silicate, we derived estimates of particulate organic carbon (POC) sinking and net diatom growth. Our results indicate that nutrients delivered from the watershed to the estuary during winter and spring supported >100% of the spring phytoplankton bloom. The spring bloom, which subsequently sinks across the pycnocline to the bottom layer, was decomposed in May-September to support 50 to 90% of annual bottom-layer NH4+, PO43-, and silicate regeneration. Sinking POC from surface waters accounted for 50 to 100% of bottom-layer respiration in the middle estuary, with deficits partially compensated by organic carbon delivered in landward flowing bottom water. Lateral transport of POC to the central channel from adjacent shallow waters was required to meet bottom water respiratory demands. Bottom-layer regeneration and subsequent upward transport of nutrients were sufficient to support 70 to 80% of summer rates of net organic production in surface layers. Pelagic and benthic processes were most tightly linked in the middle estuary, which is highly productive and does not interact strongly with adjacent waters. Elevated nutrient inputs to the estuary associated with high freshwater flow enhanced chlorophyll a, net O2 production, and net DIN uptake in surface layers; however, muted effects of flow on bottom-layer processes suggest that much of the increased organic production in surface layers during high flow is transported to seaward regions.