Improving water quality to provide freshwater is an urgent requirement for regional and even global social development. More accurate simulation of non-point sources pollution, monitored mainly by total nitrogen (TN) and total phosphorus (TP), has always been a challenge for InVEST water purification model, particularly in agricultural areas. This can be attributed to the fact that there is no reference data for TN and TP to rectify the outcomes modelled by this model. This paper provided these data to rectify simulation results of TN and TP to ensure their accuracy. The Huai River watershed (HRW) is an important grain production area with slow economic development, and non-point source pollution has exceeded point-source pollution. There is an urgent need for water management authorities to obtain complete spatio-temporal data on TN and TP loads and their exports to improve water quality. The reference data onloads and exports of TN and TP were estimated for the entire watershed and its sub-watersheds through an investigation-evaluation technique during 1980–2018. TN and TP loads generated from the agricultural sector were the major pollution sources in the HRW and had similar time trends during the same period. The spatial distribution of TN and TP exports was modelled byusingthe InVEST water purification model, and it was found that the temporal trends for the final exports of TN and TP into river systems were similar to those for TN and TP loads in the HRW for 1980–2018. Key driving factors were detected using the Geo-detector method to quantify the contribution rates of factors to the spatiotemporal exports of TN and TP. Our results showed that individual factors, such as precipitation and land use/cover, were the most important factors driving spatio-temporal variations in TN and TP exports in the HRW from 1980 to 2018. Meanwhile, the contribution rates of interactions between land use/cover and other factors were consistently highest in this watershed during the same period. In this study, we estimated the loads and exports of TN and TP, and modelled their spatial patterns in this watershed from 1980 to 2018, providing important information on TN and TP for water-related management authorities. We also provide a method for other river systems to calibrate the parameters in the biophysical table of InVEST water purification model based on final exports of TN and TP.