Objective To explore the predictive value of superoxide dismutase (SOD) and serum amyloid A (SAA) in short-term poor prognosis in patients with lacunar infarction. Methods The clinical data of 185 patients who were diagnosed with lacunar infarction in the Second Affiliated Hospital of Wannan Medical College between January 1st and December 31st, 2021 were analyzed retrospectively. According to the modified Rankin Scale (mRS) score 3 months after discharge, the patients were divided into the good prognostic group (mRS≤2) and the poor prognostic group (mRS>2). Multiple logistic regression was used to analyze the independent risk factors of the short-term adverse prognosis of patients with lacunar infarction, and a risk prediction model (nomograph) was constructed. The predictive efficacy of SOD, SAA and nomograph for poor prognosis was analyzed by using the receiver operating characteristic curve. Calibration curve and decision curve analysis were used to evaluate the differentiation and clinical application value of the model. Results A total of 185 lacunar cerebral infarction patients with a mean age of (68.26±10.77) years were enrolled in this study, among whom 80 (43.2%) were males and 39 (21.1%) had adverse prognosis. Multiple logistic regression analysis showed that systolic blood pressure [odds ratio (OR)=1.028, 95% confidence interval (CI) (1.004, 1.052), P=0.021], diabetes [OR=4.939, 95%CI (1.703, 14.320), P=0.003], SAA [OR=1.089, 95%CI (1.052, 1.128), P<0.001], apolipoprotein B [OR=7.647, 95%CI (2.186, 26.753), P=0.001] were independent risk factors for poor prognosis in lacunar infarction patients, while the level of SOD [OR=0.979, 95%CI (0.965, 0.994), P=0.006] was a protective factor. The area under the curve of the nomograph for predicting the short term poor prognosis was 0.874 [95%CI (0.812, 0.936), P<0.001]. The goodness-of-fit test with the calibration curve indicated that the prediction probability was consistent with the actual occurrence probability (Hosmer-Lemeshow test P=0.295), and the decision curve indicated that the nomograph had good clinical application value. Conclusion SAA and SOD have good predictive value for short-term adverse prognosis of lacunar cerebral infarction patients, and the nomograph constructed based on them has a good differentiation and consistency, which can provide a basis for clinicians to evaluate the prognosis of lacunar cerebral infarction patients.