The spatiotemporal variation of phytoplankton and their relationship with environmental variables were analyzed in the Saigon River-a tropical river in Southern Vietnam. Two longitudinal profiles were conducted during dry and rainy season at 18 sampling sites covering more than 60 km long in the river. Besides, a biweekly monitoring conducted in the upstream, urban area (Ho Chi Minh City-HCMC), and downstream of Saigon River was organized from December 2016 to November 2017. The major phytoplankton were diatoms (e.g., Cyclotella cf. meneghiniana, Leptocylindrus danicus, Aulacoseira granulata), cyanobacteria (Microcystis spp., Raphidiopsis raciborskii, Pseudanabaena sp.), and euglenoids (Trachelomonas volvocina). Commonly freshwater phytoplankton species and sometimes brackish water species were dominant during the monitoring. Phytoplankton abundances in dry season were much higher than in rainy season (>100 times) which was explained by a shorter riverine water residence time and higher flushing capacity during the dry season. There was a clear separation of phytoplankton abundance between the urban area and the remaining area of Saigon River because of polluted urban emissions of HCMC. Redundancy analysis shows that the environmental variables (TOC, nitrogen, pH, salinity, Mo, Mn) were the driving factors related to the dominance of L. danicus and Cyclotella cf. meneghiniana in the upstream river and urban section of Saigon River. The dominance of cyanobacterium Microcystis spp. in the downstream of Saigon River was related to higher salinity, Mg, Cu concentrations, and lower concentrations of nutrients, Mn, Co, and Mo. The dominance of potentially toxic cyanobacteria in Saigon River possesses health risk to local residents especially upon the increasing temperature context and nutrient loading into the river in the next decades.