Neuroinflammation is crucial for the pathophysiological hallmarks of many neurodegenerative disorders. Hyperactivated microglia has long been implicated as a detrimental player in regulating unresolvable inflammatory insults which cause damage to neurons. In the context of acrylamide (ACR) neurotoxicity, microglia activation is documented to correlate with ACR-adduct formation in the presynaptic neurons. Thus, inhibition of inflammatory mediators through vital candidate is greatly warranted to retard the disease progression. In the present study, we investigated, whether vitexin, a C-glycosylated flavone, with anti-inflammatory activity, could inhibit ACR-induced neuroinflammation-like behavior in zebrafish larvae. ACR was exposed at a dose 1 mM to 3 days post fertilization (dpf) zebrafish larvae for 3 days, whereas vitexin (10 μM) was treated for 24 h. After vitexin treatment, a series of histopathology, behavioral tests and molecular analyses were measured. Our data show that ACR larvae exhibited abnormal morphologies in brain cartilage and histological patterns. At behavioral levels, motor function was altered while the expression of pro-inflammatory mediator levels was markedly up-regulated in ACR larvae. Further, we validated the enhanced CDK5 activity is known to trigger microglia activation, also we found reduced expressions of neuroplasticity (CREB1 and ATF1) and antioxidant response makers (Nrf2, SOD-1 and CAT) in ACR intoxicated larvae. Interestingly, vitexin treatment markedly alleviated ACR-induced histological and behavioral changes in zebrafish larvae. Moreover, vitexin effectively inhibited CDK5 expression, and also hampered the release of pro-inflammatory mediators in ACR larvae. Finally, vitexin treatment rescued the loss of neuroplasticity markers along with enhanced antioxidant markers in ACR larvae. Taken together, results in the present study showed the possibility of vitexin as a potential therapeutic drug in the suppression of neuroinflammation.