Objective To evaluate the risk factors for cognitive impairment and their interactions in acute ischemic stroke (IS) patients. Methods IS patients admitted to the Department of Neurology, the People’s Hospital of Mianyang between January 2019 and January 2022 were selected. Patients were divided into a cognitive impairment group and a cognitive normal group. The demographic characteristics and clinical data of the subjects were collected, and the traditional risk factors for cognitive impairment were determined by univariate and multivariate logistic regression analysis. The multifactor dimensionality reduction test was used to detect the possible interactions between risk factors. Results A total of 255 patients were included. Among them, 88 cases (34.5%) in the cognitive impairment group and 167 cases (65.5%) in the cognitive normal group. The results of factor logistic regression analysis showed that after adjusting for covariates, big and medium infarction volume, severe IS, moderate to severe carotid artery stenosis as well as high hypersensitive C-reactive protein (hs-CRP) were associated with post-IS cognitive impairment (P<0.05). The cognitive impairment increased by 22.632 times [odds ratio=22.632, 95% confidence interval (5.980, 85.652), P<0.001] in patients with big and medium infarction volume, severe IS and high hs-CRP. Conclusions The cognitive impairment is common in acute IS. Patients with big and medium infarction volume, non-mild stroke, carotid artery stenosis, high hs-CRP, and non-right sided infarction are prone to cognitive impairment, and there are complex interactions among these risk factors.