Cheliff River is the most important permanent river of North-west Algeria which plays an essential role for irrigation and drinking water supply, but suffers from high anthropogenic pressure. Multi-dimensional and multi-factorial aspects of water pollution in Cheliff River and its tributary Mina River were evidenced during two contrasting climatic seasons. Urban discharges were identified as a major source of water organic pollution. The inputs of untreated sewages were characterized by maximum concentrations of tryptophan-like (5.7 µmol l−1) and tyrosine-like (9.8 µmol l−1) compounds during the dry period, confirming these amino acids as fingerprints of untreated urban discharges. The synchronous monitoring and assessment of physicochemical parameters, fluorescent organic compounds and metallic elements of Cheliff River waters highlighted its global contamination, mainly in its downstream part. Cheliff River was mainly affected by organic pollution with maximum COD (1536 mg O2 l−1) and BOD5 (12 mg O2 l−1) during the wet period, and by metallic contamination with maximum Fe (287 ± 4.4 µg l−1) and Al (422.4 ± 9.4 µg l−1) during the dry period, exceeding the guideline limits. This chronic contamination was related to untreated domestic sewages, agricultural effluents and technical landfill center discharges in this area. Diffuse pollutions were also evidenced, which made the identification of different contamination sources complicated. Mina River was mostly affected by non-treated domestic sewages with maximum COD (3161 mg O2 l−1) during the wet period and maximum BOD5 (12 mg O2 l−1) during the dry period, exceeding the guideline limits. The correlation Li/Sr showed the contribution of natural influence from saline soils of Mina valley, particularly during the dry period.