AbstractUnderstanding the influence of treated wastewater reuse for irrigation on nitrate groundwater contamination in karstic landscape is critical for developing long‐term management plans and assessing the sustainability of these practices. The Pennsylvania State University has been operating a secondary treated wastewater effluent irrigation site—the “Living Filter”—since the 1960s. The objective of this study is to develop a regional groundwater flow and nitrate transport model to assess the impact of treated wastewater and disposal of large volumes of wastewater for irrigation of agricultural and forested lands on nitrate groundwater contamination in a karst landscape in the Spring Creek Watershed in central Pennsylvania. The modular three‐dimensional finite‐difference ground‐water flow model (MODFLOW) was used to construct the groundwater flow model of the local aquifer and simulate three‐dimensional regional changes in the water table over time. The simulation of nitrate fate and transport in the aquifer was conducted by developing a groundwater mass transport model using MODFLOW and a modular three‐dimensional transport multi‐species model (MT3DMS). The calibrated groundwater model yielded a root mean square error of 5.41 ft for the area of irrigation and 24.67 ft for the entire modeled area. Results of the calibrated model show the extension of a nitrate plume over most of the study area with concentrations below 10 mg·L−1 under the current 2015 setting and the long‐term 2035 scenario of increased irrigation rates. The nitrate migration was dominated by the presence of two high conductivity groundwater troughs adjacent to the study area resulting in a near steady‐state total mass since the 1990s.