Objective To explore the effect of Xingnao Kaiqiao acupuncture on depressive behavior in poststroke depressed rats by adjusting the P2X7 receptor (P2X7R) / NOD-like receptor family pyrin domain containing 3 (NLRP3) / interleukin-1β (IL-1β) pathway. Methods A post-stroke depression rat model was constructed and rats were divided into model, positive control (fluoxetine), acupuncture, pathway inhibitor (CBBG), and acupuncture+ pathway activator ( acupuncture + BzATP ) groups. Healthy rats were included as control group. Depression-like behavior was detected by sugar preference test and open field test. Serum inflammatory and oxidative stress factors were measured by enzyme-linked immunosorbent assay. Pathological changes in hippocampal tissue were detected by hematoxylin-eosin and Nissl body staining. Neuronal apoptosis in hippocampal tissue was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, and P2X7R, NLRP3, IL-1β, ionized calciumbinding adapter molecule 1 (Iba-1), B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X (Bax), and cleaved caspase3 proteins in hippocampal tissue were detected by Western blot. Results Compared with control group, rats in model group showed decreased glucose preference and open field activity distance, pathological damage to brain tissue, increased serum inflammatory factors, malondialdehyde ( MDA), and proportion of neuronal apoptosis, decreased catalase ( CAT) activity, increased levels of P2X7R/ NLRP3 / IL-1β pathway proteins, Iba-1, and pro apoptotic proteins in hippocampal tissue, and decreased anti-apoptotic proteins (P<0. 05). Compared with model group, rats in the model, fluoxetine, acupuncture, and CBBG groups showed increased glucose preference and open field activity distance, reduced pathological damage in hippocampal tissue, increased number of Nissl bodies, decreased levels of serum inflammatory factors, MDA, and proportion of neuronal apoptosis, increased CAT activity, decreased levels of P2X7R/ NLRP3 / IL-1β pathway proteins, Iba-1, and pro apoptotic proteins in hippocampal tissue, and increased antiapoptotic proteins (P<0. 05). Compared with acupuncture group, rats in the acupuncture + BzATP group showed aggravated depressive behavior, clear pathological damage to hippocampal tissue, and a decrease in the number of Nissl bodies, as well as inflammation and oxidative stress reactions, increased levels of P2X7R/ NLRP3 / IL-1β pathway proteins, Iba-1, and pro-apoptotic proteins, and decreased levels of anti-apoptotic proteins decreased (P<0. 05). Conclusions Xingnao Kaiqiao acupuncture may alleviate inflammation and the oxidative stress response and inhibit neuronal apoptosis in rats by regulating the P2X7R/ NLRP3 / IL-1β pathway, thereby improving hippocampal tissue damage and exerting antidepressant effects.