Aim To investigate the expression of serum microRNA (miRNA) miR-181c and miR-128b in patients with cerebral infarction and its correlation with 90-day prognosis, and provide reference for the diagnosis and treatment of cerebral infarction. Methods 128 patients with cerebral infarction admitted to our hospital from January 2015 to June 2018 and 108 healthy subjects in the same period were selected as study subjects and control groups. The expression levels of miR-181c and miR-128b were compared between the two groups, and the correlation between miR-181c, miR-128b expression levels and disease severity, as well as risk factors associated with cerebral infarction were analyzed. According to the prognosis of 90 days follow-up, the good prognosis group and the poor prognosis group were classified, and the factors affecting the prognosis of 90 d were analyzed by single factor and logistic regression analysis to explore the independent influencing factors affecting the occurrence and prognosis of the disease. Results The smoking, hyperlipidemia, hypertension, diabetes and atrial fibrillation rate in the study group were significantly higher than those in the control group (P<0.05), and the expression levels of miR-181c and miR-128b in the study group were significantly higher than those in the control group (P<0.05). Logistic regression analysis showed that the diabetes and expression levels of miR-181c and miR-128b were independent risk factors for cerebral infarction (P<0.05); Spearman correlation analysis showed that the severity of acute cerebral infarction was positively correlated with serum miR-181c and miR-128b levels (r=0.867, P=0.005; r=0.885, P=0.002); The incidence of hypertension, diabetes, atrial fibrillation, NIHSS score at admission, and serum miR-181c and miR-128b levels were significantly higher in patients with poor prognosis than those with good prognosis (P<0.05). Conclusion Logistic regression analysis showed that NIHSS score and serum miR-181c and miR-128b levels were significantly correlated with the 90-day prognosis of patients with acute cerebral infarction.