Very little is known about the composition and the annual cycle of zooplankton assemblages in the Red Sea, a confined water body characterized by a high biodiversity and endemism but at the same time one of the most understudied areas in the world in terms of marine biodiversity. This high diversity together with the lack of references for several of the groups poses a problem in obtaining basic information on zooplankton seasonal patterns. In the present work, we used high throughput sequencing to examine the temporal and spatial distribution of the zooplankton communities inhabiting the epipelagic zone in the central Red Sea. The analysis of zooplankton assemblages collected at two sites—coastal and offshore—twice a month at several depth strata by using MANTA, Bongo and WP2 nets provides baseline information of the seasonal patterns of the zooplankton community over 1 year. We show that the seasonal fluctuation of zooplankton communities living in the upper 100 m of the water column is driven mainly by the annual changes in seawater temperature. The 18S rRNA gene was used for metabarcoding of zooplankton assemblages revealing 630 metazoan OTUs (97% similarity) in five phyla, highlighting the richness of the Red Sea community. During colder months, communities were characterized by lower richness and higher biomass than communities found during the hot season. Throughout the year the zooplankton communities were dominated by the class Maxillopoda, mainly represented by copepods and class Hydrozoa. The rise in the water temperature favors the appearance of classes Malacostraca, Cephalopoda, Gastropoda, and Saggitoidea. The present study provides essential baseline information for future monitoring and improves our knowledge of the marine ecosystem in the Red Sea while reporting the main environmental variable structuring zooplankton assemblages in this region.