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Purpose: To investigate the effect and mechanism of oridonin in chronic unpredictable mild stress (CUMS)-induced depressive-like behaviors. Methods: CUMS was established using 6-week stress stimuli, including feed/water deprivation, night lighting, inverted light/dark cycle, and tail clamping. Depressive behaviors were analyzed using the sucrose preference test, forced swim test (FST), and tail suspension test (TST). Locomotor activity was analyzed using the open field test (OFT) while inflammatory cytokines were analyzed by enzyme-linked immunosorbent assay. The activation of the TXNIP/NLRP3 signaling pathway was evaluated by western blot. Results: Sucrose consumption of CUMS-treated mice was significantly decreased, while immobility times of the FST (control vs. CUMS, ~50 to 150 s; p < 0.01) and TST (Control vs. CUMS, ~50 to 130 s; p < 0.01) were increased; oridonin significantly reversed these effects. Spontaneous locomotor activities (crossing, rearing, and grooming) measured in the OFT were decreased after the CUMS procedure, and oridonin increased these activities (p < 0.01 vs. CUMS). Oridonin decreased the production of tumor necrosis factor alpha, interleukin (IL)-1β, IL-6, and monocyte chemoattractant protein-1 in the hippocampus of CUMS-treated mice and significantly inhibited activation of the TXNIP/NLRP3 pathway induced by CUMS. Conclusion: Oridonin ameliorates depressive-like behaviors in mice induced by CUMS, partly via TXNIP/NLRP3 signaling pathway. Thus, the findings provide evidence for the potential application of oridonin in depression therapy. [ABSTRACT FROM AUTHOR]