Objective: To explore the predictive value of P-Selectin and Pentraxin 3 (PTX3) levels in patients with nonvalvular atrial fibrillation (NVAF) complicated with ischemic stroke using ROC curve analysis. Methods: Selected 48 patients with NVAF and ischemic stroke admitted to the hospital from June 2018 to December 2020 as the occurrence group, and 50 patients with NVAF without ischemic stroke during the same period as the nonoccurrence group. Clinical data of the two groups were collected. Serum CD62P and PTX3 levels were detected and compared between the two groups. Logistic regression analysis was used to analyze the risk factors for ischemic stroke in patients with NVAF, and the receiver operating characteristic curve (ROC) was used to evaluate the predictive value of serum CD62P and PTX3 levels for ischemic stroke in patients with NVAF. Results: The age, left atrial diameter (LAD), CHA2DS2VASc score, and serum CD62P and PTX3 levels of patients in the occurrence group were higher than those in the nonoccurrence group (P < 0.05). Logistic regression analysis showed that serum CD62P and PTX3 levels, CHA2DS2VASc score, LAD, and age were risk factors for ischemic stroke in patients with NVAF (P < 0.05). ROC analysis showed that the sensitivity, specificity, accuracy, and area under the curve (AUC) of serum CD62P and PTX3 in predicting ischemic stroke in NVAF patients were 80.72%/83.54%, 77.31%/74.29%, 79.35%/81.41%, and 0.769/0.787, respectively. The sensitivity, specificity, accuracy, and AUC of the combined prediction of the two were 90.36%, 68.75%, 87.91%, and 0.854, respectively. Conclusion: The abnormal increase in serum CD62P and PTX3 levels is related to NVAF patients complicated with ischemic stroke, and serum CD62P and PTX3 are risk factors for ischemic stroke in NVAF patients. The combination of the two has high clinical value in predicting ischemic stroke in NVAF patients.