Large watercourses are characterised by significant spatial and temporal changes in water quality due to both natural and anthropogenic impacts. The paper analyses changes in the Danube’s spatial and seasonal water quality in its middle part at five monitoring stations for the period 2018–2022. Examined water quality parameters include oxygen saturation (Os), ammonium (N-NH4), pH, 5-day biochemical oxygen demand (BOD), nitrate nitrogen (N-NO3), orthophosphates (P-PO4), suspended solids (SS), electrical conductivity (EC), and water temperature (WT). Furthermore, the analysis took into account the influence of two additional factors: air temperature (AT) and discharge (D). Throughout the entire period under study, all parameters were characterised by low concentration values, which met the environmental objective of good ecological status. The use of multivariate statistical methods allowed for the identification of EC, N-NH4, WT, Os, SS, and N-NO3 as determining the greatest spatio-seasonal variability of water quality in a selected section of the Danube. Regression models determined WT, EC and nitrogen nitrate changes as depending on AT, flow, and exposure time. Knowing models not only gives a better understanding of the dynamics of changes in water quality in the stretch of the Danube under study but potentially allows the prediction of these parameters based on easily measurable environmental variables.