A groundwater plume containing high concentrations of pharmaceutical compounds, mainly sulfonamides, barbiturates, and ethyl urethane, in addition to chlorinated ethenes and benzene was investigated. The contamination originating from a former pharmaceutical industry discharges into a multilayered aquifer system and a downgradient stream. In this study, geological and hydrogeological data were integrated into a numerical flow model to examine identified trends using statistical approaches, including principal component analysis and hierarchal cluster analysis. A joint interpretation of the groundwater flow paths and contaminant concentrations in the different compartments (i.e., groundwater and hyporheic zone) provided insight on the transport processes of the different contaminant plumes to the stream. The analysis of historical groundwater concentrations of pharmaceutical compounds at the site suggested these compounds are slowly degrading. The pharmaceutical compounds migrate in both a deep semiconfined aquifer, as well as in the shallow unconfined aquifer, and enter the stream along a 2‐km stretch. This contrasted with the chlorinated ethenes, which mainly discharge to the stream as a focused plume from the unconfined aquifer. The integrated approach developed here, combining groundwater flow modeling and statistical analyses of the contaminant concentration data collected in groundwater and the hyporheic zone, lead to an improved understanding of the observed distribution of contaminants in the unconfined and semiconfined aquifers, and thus to their discharge to the stream. This approach is particularly relevant for large and long‐lasting contaminant sources and plumes, such as abandoned landfills and industrial production sites, where field investigations may be very expensive.