Objective: To explore the effect of Xingnao Kaiqiao acupuncture on depressive behavior in post-stroke depressed rats by adjusting P2X7 purinergic receptor (P2X7R)/NOD-like receptor family pyrin domain containing 3 (NLRP3)/interleukin-1β (IL-1β) pathway. Methods: A post-stroke depression model rat was constructed and grouped into a model group, a positive control group (fluoxetine group), an acupuncture group, a pathway inhibitor group (CBBG group), and an acupuncture+pathway activator group (acupuncture+BzATP group). Healthy rats were included as the control group. The depression like behavior (sugar preference test, open field test), serum inflammatory and oxidative stress factors (ELISA method), pathological changes in hippocampal tissue (HE staining, Nissl body staining), neuronal apoptosis in hippocampal tissue (TUNEL method), and the P2X7R, NLRP3, IL-1β, Iba-1, Bcl-2, Bax, and cleaved caspase3 proteins in hippocampal tissue (Western blot method) were detected. Results: For the control group, the model group showed a clear decrease in glucose preference and open field activity distance in rats, clear pathological damage to brain tissue, a clear increase in serum inflammatory factors, MDA, and proportion of neuronal apoptosis, a clear decrease in CAT activity, a clear increase in P2X7R/NLRP3/IL-1β pathway proteins, Iba-1, and pro apoptotic proteins in hippocampal tissue, and a clear decrease in anti apoptotic proteins (P<0.05). For the model group, the fluoxetine, acupuncture, and CBBG groups showed an increase in glucose preference and open field activity distance in rats, reduced pathological damage in hippocampal tissue, increased number of Nissl bodies, a decrease in serum inflammatory factors, MDA, and proportion of neuronal apoptosis, an increase in CAT activity, a decrease in P2X7R/NLRP3/IL-1β pathway proteins, Iba-1, and pro apoptotic proteins in hippocampal tissue, and an increase in anti apoptotic proteins (P<0.05). For the acupuncture group, the acupuncture+BzATP group showed showed aggravated depressive behavior, clear pathological damage to hippocampal tissue, and a decrease in the number of Nissl bodies in rats, the inflammation and oxidative stress reactions occurred in the body, the P2X7R/NLRP3/IL-1β pathway proteins, Iba-1, and pro apoptotic proteins increased, while the anti apoptotic proteins decreased (P<0.05). Conclusion: The Xingnao Kaiqiao acupuncture may alleviate inflammation and oxidative stress response, inhibit neuronal apoptosis in rats by adjusting P2X7R/NLRP3/IL-1β pathway, thereby improving hippocampal tissue damage and exerting antidepressant effects.