Objective To explore the relationship between the ratio of monocyte to high-density lipoprotein cholesterol (MHR), neutrophil to lymphocyte (NLR) and the prognosis of patients with acute ischemic stroke undergoing intravenous thrombolysis. Methods A retrospective analysis was conducted on the medical records of 110 patients with acute ischemic stroke admitted to the First People's Hospital of Bengbu from January 2021 to December 2022. Baseline data was collected, and according to the 90 day telephone follow-up of patients, they were divided into a good prognosis group and a poor prognosis group, and high-risk factors that affect the patient's prognosis were screened. High risk factors affecting patient prognosis were screened, and the predictive efficacy of MHR and NLR on the prognosis of patients with acute ischemic stroke undergoing intravenous thrombolysis was evaluated. Results Among 110 patients with acute ischemic stroke, 76 had a good prognosis (69.09%) and 34 had a poor prognosis (30.91%). The white blood cell count, National Institutes of Health Stroke Scale (NIHSS) score, MHR, and NLR levels of patients with poor prognosis were higher than those of patients with good prognosis. The logistic analysis results showed that an increase in white blood cell count (OR=4.125, 95% CI: 1.409-12.068), an increase in NIHSS score (OR=4.860, 95% CI: 1.662-14.218), an increase in MHR (OR=3.445, 95% CI: 1.178-10.079), and an increase in NLR (OR=4.043, 95% CI: 1.382-11.829) were all factors affecting the poor prognosis of acute ischemic stroke patients (P<0.05). The results of receiver operating characteristic (ROC) analysis showed that the sensitivities of single and combined MHR and NLR in predicting the outcome of acute ischemic stroke patients were 0.824 (0.648-0.926), 0.794 (0.616-0.907), 0.853 (0.682-0.944); The specificity was 0.763 (0.649-0.850), 0.763 (0.649-0.850), 0.882 (0.782-0.941); The areas under the curve (AUC) were 0.790 (0.712-0.869), 0.801 (0.732-0.891), 0.875 (0.810-0.940), respectively. Conclusion The levels of MHR and NLR are closely related to the prognosis of patients with acute ischemic stroke, and can be used to predict the short-term prognosis of patients.