Nitrogen loading from agricultural landscapes can trigger a cascade of detrimental effects on aquatic ecosystems. Recently, the spread of aquatic weed infestations (Eichhornia crassipes, Egeria densa, Ludwigia spp., and Onagraceae) in the Sacramento-San Joaquin Delta of northern California has raised concerns, and nitrogen loading from California’s intensive farming regions is considered as one of the major contributors. In this study, we employed the Soil and Water Assessment Tool (SWAT) to simulate nitrogen exports from the agriculturally intensive San Joaquin River watershed to the Delta. The alternate tile drainage routine in SWAT was tested against monitoring data in the tile-drained area of the watershed to examine the suitability of the new routine for a tile nitrate simulation. We found that the physically based Hooghoudt and Kirkham tile drain routine improved model performance in representing tile nitrate runoff, which contributed to 40% of the nitrate loading to the San Joaquin River. Calibration results show that the simulated riverine nitrate loads matched the observed data fairly well. According to model simulation, the San Joaquin River plays a critical role in exporting nitrogen to the Delta by exporting 3135 tons of nitrate-nitrogen annually, which has a strong ecological implication in supporting the growth of aquatic weeds, which has impeded water flow, impairs commercial navigation and recreational activities, and degrades water quality in Bay-Delta waterways. Since nitrate loadings contributed by upstream runoff are an important nutrient to facilitate weed development, our study results should be seen as a prerequisite to evaluate the potential growth impact of aquatic weeds and scientific evidence for area-wide weed control decisions.