Recently, concerns about the toxicity of microplastics (MPs) pollution have attracted significant attention. However, the influence of hydrodynamics on MPs bioaccumulation in fish, and the associated risks, remains poorly understood. Therefore, this study addressed this critical knowledge gap by examining how water velocity, individual and in combination with MPs, impacts brain in juvenile grass carp (Ctenopharyngodon idella). Fish were exposed for seven days (28 h total, with 2-h sessions twice daily) to 5 µm polystyrene MPs (PS-MPs) at an environmentally relevant concentration of 1000 µg/L across eight groups: control, low (LV), medium (MV), and high (HV) water velocity, MPs-only, and three combined treatments (MPs + each velocity level). Fish exposed to the MPs + HV group illustrated the highest accumulation of PS-MPs with a concentration of 33.94 ± 1.00 × 10³ μg/kg (p < 0.05) and exhibited more brain damage, including hemorrhage, edema, and tissue rupture. Furthermore, this group demonstrated significantly increased superoxide dismutase (SOD) and lipid peroxidation (LPO) activities, along with significant reduction in acetylcholinesterase (AChE) activity (p < 0.05), providing clear evidence of oxidative stress and neurotoxicity. Transcriptomic analysis showed a significant variation in gene expression with associated key pathways such as DNA repair, RNA transport, FoxO signaling, and MAPK signaling, indicating active cellular responses to genetic damage. Overall, this study highlighted the critical role of hydrodynamics in MPs bioaccumulation in fish and the compounded risks of MPs and water velocity, emphasizing the crucial need for monitoring of MPs pollution in dynamic aquatic environments, particularly in riverine systems.