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Alberta has over 70% of total irrigated land in Canada and 13 irrigation districts are mainly located along the rivers in southern Alberta. The runoff and irrigation return flow can carry excess nutrients, pesticides, and sediments, which adversely affect the river water quality. In the present study, the comprehensive spatiotemporal analysis of land use pattern and stream water quality in southern Alberta was conducted. The water quality monitoring on the South Saskatchewan River watershed within Alberta showed that most water quality indicators did not significantly change between 2003 and 2017. Land use maps demonstrated significant urban expansion and cropland decline in the study area from 2005 to 2015, while the irrigation area increased. Correlation analysis and redundancy analysis revealed that cropland, built-up land, and native grassland were three land use types that were positively correlated with water quality indicators. Stronger correlations between nitrogen concentration and built-up land were found in dry seasons compared with wet seasons. According to the results of cluster analysis, higher water quality indicator concentrations could be observed in groups with a higher proportion of cropland and built-up land. Significant relationships between land use patterns and water quality were found in this study, which demonstrated that further investigation is needed to identify the sources of water pollutants at a smaller scale.