In this study, we investigated the mechanism of eutrophication and hypoxia in the upper Gulf of Thailand from August 2014 to June 2015 based on field observation data, box model analysis, and the unscaled trophic status index (UNTRIX). Fresh water residence time derived from a simple box model was long (38.61 days) during the transition period between the southwest to northeast monsoon in September 2014. In contrast, fresh water residence time was short (2.63 days) during the late northeast monsoon in February 2015. Long residence time was related to the development of widespread strong hypoxia in near-bottom waters in over half of the gulf during the transition between the southwest and the northeast monsoon, when river discharge was also very large. UNTRIX is used to assess water trophic levels, and is based on water qualities including concentrations of chlorophyll-a (Chl-a), dissolved oxygen (DO), dissolved inorganic nitrogen (DIN), and dissolved inorganic phosphorus (DIP). Hypertrophic and eutrophic conditions were observed at river mouths; their seasonal eutrophication was related to river discharge and circulation. Nutrients were mainly increased by river discharge. Water column stratification and long residence time were required for the development of severe hypoxia in the study area.