We developed a process model LM3-TAN to assess the combined effects of direct human influences and climate change on terrestrial and aquatic nitrogen (TAN) cycling. The model was developed by expanding NOAA's Geophysical Fluid Dynamics Laboratory land model LM3V-N of coupled terrestrial carbon and nitrogen (C-N) cycling and including new N cycling processes and inputs such as a soil denitrification, point N sources to streams (i.e., sewage), and stream transport and microbial processes. Because the model integrates ecological, hydrological, and biogeochemical processes, it captures key controls of the transport and fate of N in the vegetation–soil–river system in a comprehensive and consistent framework which is responsive to climatic variations and land-use changes. We applied the model at 1/8° resolution for a study of the Susquehanna River Basin. We simulated with LM3-TAN stream dissolved organic-N, ammonium-N, and nitrate-N loads throughout the river network, and we evaluated the modeled loads for 1986–2005 using data from 16 monitoring stations as well as a reported budget for the entire basin. By accounting for interannual hydrologic variability, the model was able to capture interannual variations of stream N loadings. While the model was calibrated with the stream N loads only at the last downstream Susquehanna River Basin Commission station Marietta (40°02' N, 76°32' W), it captured the N loads well at multiple locations within the basin with different climate regimes, land-use types, and associated N sources and transformations in the sub-basins. Furthermore, the calculated and previously reported N budgets agreed well at the level of the whole Susquehanna watershed. Here we illustrate how point and non-point N sources contributing to the various ecosystems are stored, lost, and exported via the river. Local analysis of six sub-basins showed combined effects of land use and climate on soil denitrification rates, with the highest rates in the Lower Susquehanna Sub-Basin (extensive agriculture; Atlantic coastal climate) and the lowest rates in the West Branch Susquehanna Sub-Basin (mostly forest; Great Lakes and Midwest climate). In the re-growing secondary forests, most of the N from non-point sources was stored in the vegetation and soil, but in the agricultural lands most N inputs were removed by soil denitrification, indicating that anthropogenic N applications could drive substantial increase of N2O emission, an intermediate of the denitrification process.