Understanding the relationship between the zooplankton distribution and salinity may provide key information to understand ecosystem function under the condition of a global mean sea level rise caused by global climate change. However, little is known about how increasing salinity level will affect the entire zooplankton community on a large scale. Here we completed 1 year of field investigations on the Pearl River Estuary and analyzed the distribution and structure of the zooplankton community. A total of 68 zooplankton species were identified during the survey. The number and diversity (richness, evenness, Shannon index, and Simpson’s index) of the zooplankton species decreased as salinity increased from 0.10 to 21.26. Salinity negatively affected the abundances of rotifers, cladocerans, and total zooplankton, while it had little effect on copepod abundance. Some salt-tolerant species, such as Keratella tropica, Polyarthra vulgaris, and Paracalanus crassirostris, survived at high-salinity sites. A pattern was observed at all sites: the peak in copepod abundance always occurred when rotifers were abundant (sites S1 and S2) or after rotifer abundance reached a maximum level (sites S3, S4, and S5). In general, salinity was the most important environmental factor shaping zooplankton biodiversity and abundance. This study provides insight into potential biodiversity and structure of the zooplankton community in response to salinity change.