Despite the tremendous efforts to improve river water quality, chemical contamination remains a significant issue. Besides well-known contaminants, in recent years, pollutants of industrial origin received increasing attention because of the huge knowledge gap regarding their occurrence, fate and environmental risks. Moreover, such pollutants often exhibit high concentration fluctuations over time, which makes them less predictable and measurable with classical short-time campaigns.This study provides insights into the different sources of chemical contamination of the Rhine River based on temporal high-frequency LC-HRMS monitoring data from a single location. A newly developed prioritization strategy selected nearly 3000 substances as potentially major contaminants. A novel classification analysis based on temporal behavior identified 53% of these compounds (accounting for 62% of the time-integrated intensity recorded in the dataset) as originating from irregular emission sources. Irregular emissions can originate from industrial production cycles. After delimiting other potential irregular sources, we have strong evidence indicating that a considerable share of the irregular emissions likely comes from industrial activities. This finding is supported by the structural elucidation of sixteen irregularly emitted substances, for which the industrial origin was successfully confirmed. Those compounds include 3-chloro-5-(trifluoromethyl)pyridine-2-carboxylic acid and 4-(dimethylamino)-2,2-diphenylpentanenitrile. In addition, 40 other compounds exhibited temporal emission patterns similar to the sixteen industrial compounds, which strongly suggests a common contamination source. Finally, 100 top-ranking compounds were selected for further structural elucidation and emission reduction measures. The computational approach outlined within this study can be effectively applied in other large river catchments to identify unknown contaminants stemming from industrial sources.