To investigate whether pretreatment with cake-separated moxibustion can alleviate the injury of aspirin to the gastric mucosa and reveal its potential mechanism, Sprague-Dawley rats (male and female) were randomly divided into the blank control group, model group, pretreatment acupoint group, and pretreatment control point group, 20 rats in each group. This experiment was approved by the Institutional Animal Care and Use Committee (IACUC) of Hunan Slack Jingda Laboratory Animal Co., Ltd. (approval No.: IACUC-SJA18038). From day 1 to day 8, the rats in the blank control and model groups were tied for 30 min each day, and the rats in the pretreatment acupoint group, and pretreatment control point group were tied and treated with moxibustion for 30 min each day. The rats in each group were fasted without water for 24 h after tying on days 2, 4, 6 and 8, respectively, and then gavaged at 150 mg·kg^-1 aspirin, and the gavage volume of 1 mL per 100 g body weight was injected into the stomach of the rats in the model group, pretreatment acupoint group, and pretreatment control point group, and the normal saline was injected into the stomach of the rats in the blank control group with a gavage needle at a dose of 1 mL per 100 g body weight. Gastric mucosa injury index was observed, and histology of gastric mucosa was observed by hematoxylin-eosin staining. Superoxide dismutase (SOD) and malondialdehyde (MDA) content in serum and gastric mucosa were detected by enzyme-linked immunosorbent assay. The levels of Kelch-like ECH-associated protein 1 (Keap1), nuclear factor-erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), catalase (CAT), glutathione S-transferase (GST), and NAD(P)H: quinone oxidoreductase 1 (NQO1) in gastric mucosa were detected by quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Western blot. The results showed that compared with the blank control group, the rats in the model group showed increased behavior status, emotional response, skin hair, diet status and stool status scores (P < 0.05), significantly higher gastric mucosal injury index (P < 0.05), significantly lower SOD (P < 0.05), and significantly higher MDA (P < 0.05), and significantly upregulated Keap1 expression in gastric mucosal tissues (P < 0.05), while the expression of Nrf2, HO-1, CAT, GST, and NQO1 was significantly downregulated (P < 0.05). Compared with the model group, the emotional response and sleep status scores of the rats in the pretreatment acupoint group were reduced (P < 0.05), and the gastric mucosal injury index was significantly reduced (P < 0.05), and the gastric mucosal injury in pretreatment control point group tended to be reduced, but there was no statistical difference (P > 0.05), and SOD was significantly increased (P < 0.05), while MDA was significantly decreased (P < 0.05) and the level of Keap1 was significantly decreased (P < 0.05), while the expression of Nrf2, HO-1, CAT, GST, and NQO1 was significantly upregulated (P < 0.05) in the pretreatment acupoint group and pretreatment control point group. Compared with the pretreatment control point group, the gastric mucosal injury index was significantly lower (P < 0.05), SOD was significantly higher (P < 0.05), while MDA was significantly lower (P < 0.05), Keap1 was significantly lower (P < 0.05) and Nrf2, HO-1, CAT, GST, and NQO1 were significantly higher (P < 0.05) in the pretreatment acupoint group. The above results suggested that the pretreatment of cake-separated moxibustion could activate Nrf2/antioxidant response element (ARE)/HO-1 signaling pathway, enhance the antioxidant stress ability of gastric mucosa cells, and reduce the damage of gastric mucosa caused by aspirin.