A B S T R A C T Background: Accurate diagnosis of acute appendicitis in non-pregnant women remains challenging due to overlapping symptoms with gynecological pathologies. This study compares the diagnostic performance of the Tzanakis Score (incorporating ultrasonography) and the Alvarado Score (clinical and laboratory-based) in this population. Objectives: Primary Objective To compare the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of the Alvarado and Tzanakis Score Secondary Objective To assess the diagnostic performance of both scoring systems Methods: we included retrospectively 120 non-pregnant women presenting with suspected appendicitis at Zagazig University Hospitals (July–December 2024). Both scoring systems were applied, and histopathology post-appendectomy served as the diagnostic gold standard. Sensitivity, specificity, PPV, NPV, accuracy, and ROC curves were analyzed using SPSS v20. Results: The Tzanakis Score demonstrated superior sensitivity (92% vs. 78%), specificity (88% vs. 72%), and accuracy (90% vs. 75%) compared to the Alvarado Score (p < 0.05). ROC analysis showed a larger AUC for Tzanakis (0.94 vs. 0.82). Subgroup analyses confirmed consistent performance across age and symptom severity categories. Conclusion: The Tzanakis Score, integrating ultrasonography, significantly outperforms the Alvarado Score in diagnosing acute appendicitis in non-pregnant women, reducing unnecessary surgeries and optimizing resource utilization. We recommend its adoption in settings with access to imaging.