The Mekong River Delta is a hotspot of aquaculture and fish biodiversity. In this study, fish community structure, migration, threatened status and economic value were investigated in the Co Chien River (COR) from August 2017 to July 2019. A total of 3640 fish specimens were collected from 11 sampling stations in the COR. These belong to 133 species of 107 genera of 58 families of 17 orders. The Perch-like order (Perciformes) is the most diverse group, with 65 species accounting for 48.87% of total species collected. The catfish order (Siluriformes) is the second-most diverse group with 15 species (11.28%) and the carps (Cypriniformes) with 14 species (10.53%) is the third. The remaining major groups in the order of diversity are the Herring (Clupeiformes) consisting of 9 species (6.77%) and the Flounder (Pleuronectiformes) consisting of 7 species (5.26%). The remaining orders have number of species varying from 1 to 3 (0.75–2.26%). Among the 133 species recorded, 6 species were considered as Vulnerable category based on the Vietnam Red Data Book (2007). According to the IUCN Red list (2021), 1 species (Coilia mystus) is Endangered (0.75%), 2 species (Maculabatis gerrardi and Pangasius krempfi) are Vulnerable (1.50%), 4 species are Near Threatened (3.01%), 6 species are Data deficient (4.51%), and 76 species are considered as Least concern (57.14%). The results shown that 79 species were migratory fishes (20 species migrated from the upstream and 59 species migrated from the sea), 41 species are endemic species for the MR (30.83% of the total species collected and 23.70% of total endemic species of the MR) and 36 fish species are considered as of local economic value (27.07%). The diversity of fish species was found to be more diverse in the dry season than the wet season, which indicates the influence of river water salinity changes on fish diversity in the region.