The Seine River is a highly artificialised catchment in Europe, comprising both productive agricultural areas and intense industrial and commercial activity. Due to its strategic importance, monitoring programs in the river started as early as the 1970s. The present study compiles and analyses this valuable data set (1970–2014), thoroughly describing the riverine section downstream of Paris and the estuary. We identify long-term trends and shifting patterns in nutrients and oxygen, and pay special attention to the river’s evolution after the year 2000, when the European Water Framework Directive came into force. The study has a manifest management perspective, and the results are discussed on the basis of the environmental quality standards proposed in current environmental regulations. The data show that water quality has improved remarkably over the past two decades, with sharp reductions of ammonium and phosphate and a progressive increase of dissolved oxygen levels. The amelioration is prominent in the estuary, where summer anoxic episodes have nearly disappeared. As a result, these three parameters are nowadays in good or very good condition throughout the year. The successful abatement of point sources contrasts, however, with the low effectiveness of the measures provided for the control of nutrients from diffuse sources. Nitrate concentration has increased by 150% since the early 1980s, and only very recently has the upward trend been reversed. Bold agri-environmental management measures are required if we are to prevent chronic pollution problems and truly restore the good ecological status of rivers.