Background Variceal bleeding is a life-threatening complication of cirrhosis. Traditionally, endoscopy has been utilized as a preferred modality for the detection and grading of esophageal varices. However, endoscopy is an invasive procedure and may not be readily available in resource-limited settings. To overcome this limitation, various non-invasive tests, including Doppler ultrasonography (DUS) with portal vein (PV) velocity measurement, have been investigated to predict the presence of esophageal varices (EV). This study aimed to evaluate the potential utility of portal vein flow velocity (PVFV) as a non-invasive alternative to endoscopic screening for predicting the presence of esophageal varices among cirrhotic patients. Methodology This validation cross-sectional study was carried out at the Department of Gastroenterology and Hepatology, Pakistan Kidney and Liver Institute & Research Centre (PKLI&RC), Lahore, Pakistan from June 8, 2022, to March 8, 2023. Cirrhotic patients were enrolled based on clinical, laboratory, and radiological assessments. Doppler ultrasonography was performed to measure portal vein flow velocity along other relevant indices. Subsequently, all patients underwent endoscopic evaluation to screen and grade the esophageal varices. Univariate and multivariate logistic regression analyses were performed to identify significant clinical predictors of EV based on the results of the independent sample t-tests or Mann-Whitney U tests. Receiver operating characteristic (ROC) curves were employed to determine the optimal cut-off value for portal vein flow velocity (PVFV). Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy were calculated based on the identified cut-off value. A p-value ≤ 0.05 was considered statistically significant. Results A cohort of 137 cirrhotic patients was enrolled. The study population consisted of 92 males (67.2%) and 45 females (32.8%). Endoscopic screening confirmed the presence of esophageal varices in 81 patients (59.91%). A multivariate analysis revealed that aspartate aminotransferase to platelet ratio index (APRI) (p=0.008) and portal vein flow velocity (p=0.001) were significant factors associated with esophageal varices and were used for receiver operating characteristic (ROC) analysis. The area under the curve (AUC) for PVFV was 0.981, and for APRI, it was 0.711. At a cut-off value of 18 cm/sec for PVFV, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy for esophageal varices were found to be 93.83%, 92.86%, 95%, 91.23%, and 93.43%, respectively. Conclusion Measurement of portal vein flow velocity using Doppler ultrasonography (DUS) is a reliable screening method for predicting the presence of esophageal varices (EV) in patients with liver cirrhosis. DUS offers several advantages, including its non-invasive nature, cost-effectiveness, and widespread availability, making it a recommended approach due to its high diagnostic accuracy.