Background: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) often causes various neurological sequelae, necessitating early and objective differentiation of AESD from a febrile seizure (FS). Therefore, we developed a scoring system that predicts AESD onset using only early laboratory data. Methods: We selected patients with AESD or FS admitted to the Tottori University Hospital between November 2005 and September 2020 and collected laboratory data from onset to discharge in patients with FS and from onset to the second neurological events in patients with AESD. Results: We identified 18 patients with AESD and 181 patients with FS. In comparison with patients with FS, patients with AESD showed statistically significant increases in ammonia (NH3), blood sugar (BS), and serum creatinine (Cr) levels, and the white blood cell (WBC) count, and a significant decrease in pH at <3 h from onset. We set the cut-off values and adjusted the weight of each of these parameters based on data obtained <3 h from onset and proposed a scoring system for predicting AESD. This system showed 91% sensitivity and 94% specificity for distinguishing AESD from FS. These accuracies were only slightly improved by the addition of information related to consciousness and seizure duration (sensitivity, 91%; specificity, 96%). Conclusion: NH3, BS, and Cr levels, WBC count, and pH were significantly different between patients with AESD and patients with FS at <3 h from seizure onset. This scoring system using these data may enable the prediction of AESD onset for patients under sedation or without precise clinical information.