Background: Early identification of those with NAFLD activity score ≥ 4 and significant fibrosis (≥F2) or “at-risk MASH” is a priority as these patients are at increased risk for disease progression and may benefit from therapies. We developed and validated a highly specific metabolomics-driven score to identify at-risk MASH. Methods: We included derivation (n = 790) and validation (n = 565) cohorts from international tertiary centers. Patients underwent laboratory assessment and liver biopsy for MASLD. Based on 12 lipids, body mass index, aspartate aminotransferase, and alanine aminotransferase, the MASEF score was developed to identify at-risk MASH and compared to the FibroScan-AST (FAST) score. We further compared the performance of a FIB-4 + MASEF algorithm to that of FIB-4 + liver stiffness measurements (LSM) by transient elastography (VCTE). Results: The diagnostic performance of the MASEF score showed an area under the receiver-operating characteristic curve, sensitivity, specificity, positive and negative predictive values of 0.76 (95% CI 0.72-0.79), 0.69, 0.74, 0.53, and 0.85 in the derivation cohort, and 0.79 (95% CI 0.75-0.83), 0.78, 0.65, 0.48, and 0.88 in the validation cohort, while FAST performance in the validation cohort was 0.74 (95% CI 0.68-0.79; p = 0.064), 0.58, 0.79, 0.67, and 0.73, respectively. FIB-4 + MASEF showed similar overall performance compared to FIB-4 + LSM by VCTE (p = 0.69) to identify at-risk MASH. Conclusion: MASEF is a promising diagnostic tool for the assessment of at-risk MASH. It could be used alternatively to LSM by VCTE in the algorithm that is currently recommended by several guidance publications.