Water resources are important for both human and ecological systems. However, climate change and human activities contribute to changes in water quality, impacting the health of both human and other living organisms. This chapter focuses on the trends in water quality in Bang Pakong River, Thailand. Serving a large population in eastern Thailand, this river is heavily utilized for agricultural activities. The trends of various water quality parameters were examined from upstream to downstream, encompassing both urban and agricultural areas, using Sen’s slope and Mann–Kendall test. Over a period of 28 years from 1993 to 2020, significant increases in turbidity and NH3-N along with decreases in suspended solids (SS) were observed across almost all parts of the river. Additionally, in the upstream part of the river, water temperature and biological oxygen demand (BOD) increased, while fecal coliform bacteria (FCB) decreased. In Chachoengsao, the largest urban area along this river, water quality appeared to improve in terms of dissolved oxygen (DO; increasing), total coliform bacteria (TCB; decreasing), FCB (decreasing), and SS (decreasing). However, turbidity, NO3-N, and NH3-N levels increased. Downstream from Chachoengsao, even though SS decreased similarly to other parts of the river, water quality deteriorated in many parameters such as pH, conductivity, salinity, NO2-N, NH3-N, and total dissolved solids (TDS). These varying trends in water quality across different parts of the river appear to be caused by different combinations of factors. It is suggested that implementing a sufficient wastewater treatment system and controlling aquacultural activities are necessary steps to improve water quality in the downstream area.