Kava kava (Piper methysticum) is a medicinal plant containing kavalactones that exert potent sedative, analgesic and anti-stress effects. However, their pharmacological effects and molecular targets remain poorly understood. The zebrafish (Danio rerio) has recently emerged as a powerful new model organism for neuroscience research and drug discovery. Here, we evaluate the effects of acute and chronic exposure to kava and kavalactones on adult zebrafish anxiety, aggression and sociality, as well as neurochemical, neuroendocrine and genomic responses. Supporting evolutionarily conserved molecular targets, acute kava and kavalactones evoked dose-dependent behavioral inhibition, upregulated brain expression of early protooncogenes c-fos and c-jun, elevated brain monoamines and lowered whole-body cortisol. Chronic 7-day kava exposure evoked similar behavioral effects, did not alter cortisol levels, and failed to evoke withdrawal-like states upon discontinuation. Chronic kava upregulated several microglial (iNOS, Egr-2, CD11b), astrocytal (C3, C4B, S100a), epigenetic (ncoa-1) and pro-inflammatory (IL-1β, IL-6, TNFa) biomarker genes, downregulated CD206 and IL-4 and did not affect major apoptotic genes. Collectively, this study supports evolutionarily conserved behavioral and physiological effects of kava and kavalactones in zebrafish, implicates brain monoamines in their acute effects, and provides novel important insights into potential role of neuroglial and epigenetic mechanisms in long-term kava use.