Japanese encephalitis (JE) is an arboviral disease common in Southeast Asia encompassing a population of 3 billion people. Periodic outbreak of JE takes hundreds of lives. Children are major victims of JE. About one third of JE patients die, and many of the survivors suffer from permanent neuropsychiatric sequel, owing to the lack of specific therapeutic measure. Curcumin is a naturally occurring phenolic compound extracted from Curcuma longa L. Previous studies have reported that curcumin possesses strong antioxidant, anti-inflammatory, antiviral activity. We used Neuro2a cell line and infected them with JE virus. The infected cells were treated with varying doses of curcumin. Cell viability, reactive oxygen species (ROS) production within the cells, and change in cellular membrane integrity were studied. The changes in expression of some signaling and stress-related proteins were also assessed. We also studied the inhibitory role of curcumin on the production of infective viral particles by dysregulation of the ubiquitin-proteasome system. In this study, we found that curcumin imparts neuroprotection in vitro, probably by decreasing cellular reactive oxygen species level, restoration of cellular membrane integrity, decreasing pro-apoptotic signaling molecules, and modulating cellular levels of stress-related proteins. We have also shown that curcumin, by inhibition of ubiquitin-proteasome system causes reduction in infective viral particle production from previously infected neuroblastoma cells.