Abstract: Objective To explore the application of non-invasive multimodal intracranial pressure monitoring based on optic nerve sheath diameter (ONSD) combined with transcranial color Doppler ultrasound (TCCD) midline shift in the treatment of patients with massive cerebral infarction. Methods A total of 80 patients diagnosed with massive cerebral infarction at Suqian Zhongwu Hospital from March 2021 to March 2023 were selected. According to the random number table method, they were divided into two groups (n=40): a control group (conventional monitoring) and a study group (conventional monitoring + multimodal ultrasound monitoring). Both groups were compared for general data, the proportion of patients undergoing decompressive craniectomy, and Glasgow Outcome Scale (GOS) scores at post-operation 6 months. Multivariate logistic regression analysis was conducted to explore the relationship between ONSD and TCCD midline shift monitoring values and decompressive craniectomy. The predictive value was analyzed using the ROC curve. Results There was no statistical difference in the proportion of decompressive craniectomy between the two groups (P>0.05). However, the study group showed significantly shorter length of preoperative hospitalization stay, and higher GOS scores at post-operation 6 months than the control group (P<0.05). The ONSD and TCCD midline shift values in patients undergoing decompressive craniectomy in the study group were higher than those receiving conservative therapy (P<0.05). The area under the curve (AUC) for predicting decompressive craniectomy in patients with massive cerebral infarction using ultrasound ONSD, TCCD midline shift, and their combination were 0.854, 0.748, and 0.891, respectively. Conclusions Non-invasive multimodal intracranial pressure monitoring based on ultrasound ONSD and TCCD can accurately predict decompressive craniectomy in patients with massive cerebral infarction. The measurement results have high reliability, which helps improve prognosis and is worthy of clinical promotion and application.