The Hawkesbury-Nepean River (HNR) system in South-Eastern Australia is the main source of water supply for the Sydney Metropolitan area and is one of the more complex river systems due to the influence of urbanisation and other activities in the peri-urban landscape through which it flows. The long-term monitoring of river water quality is likely to suffer from data gaps due to funding cuts, changes in priority and related reasons. Nevertheless, we need to assess river health based on the available information. In this study, we demonstrated how the Factor Analysis (FA), Hierarchical Agglomerative Cluster Analysis (HACA) and Trend Analysis (TA) can be applied to evaluate long-term historic data sets. Six water quality parameters, viz., temperature, chlorophyll-a, dissolved oxygen, oxides of nitrogen, suspended solids and reactive silicates, measured at weekly intervals between 1985 and 2008 at 12 monitoring stations located along the 300 km length of the HNR system were evaluated to understand the human and natural influences on the river system in a peri-urban landscape. The application of FA extracted three latent factors which explained more than 70 % of the total variance of the data and related to the 'bio-geographical', 'natural' and 'nutrient pollutant' dimensions of the HNR system. The bio-geographical and nutrient pollution factors more likely related to the direct influence of changes and activities of peri-urban natures and accounted for approximately 50 % of variability in water quality. The application of HACA indicated two major clusters representing clean and polluted zones of the river. On the spatial scale, one cluster was represented by the upper and lower sections of the river (clean zone) and accounted for approximately 158 km of the river. The other cluster was represented by the middle section (polluted zone) with a length of approximately 98 km. Trend Analysis indicated how the point sources influence river water quality on spatio-temporal scales, taking into account the various effects of nutrient and other pollutant loads from sewerage effluents, agriculture and other point and non-point sources along the river and major tributaries of the HNR. Over the past 26 years, water temperature has significantly increased while suspended solids have significantly decreased (p < 0.05). The analysis of water quality data through FA, HACA and TA helped to characterise the key sections and cluster the key water quality variables of the HNR system. The insights gained from this study have the potential to improve the effectiveness of river health-monitoring programs in terms of cost, time and effort, particularly in a peri-urban context.