Introduction Hypoxic-ischemic encephalopathy (HIE) is defined as a neurological complication that results from perinatal asphyxia. Previous studies had investigated various markers to early detect HIE; however, these markers appeared to have several drawbacks, especially in resource-limited settings. Aim This study aimed at evaluating the predictive value of the salivary lactate dehydrogenase level as a potential predictor of hypoxic-ischemic encephalopathy for newborns. Materials and Methods We included 30 neonates with HIE due to perinatal asphyxia and 30 healthy newborns that serve as controls, admitted at the intensive care unit for neonates and maternity ward at Ismailia area Clinics and Hospitals. We measured the LDH levels by using saliva samples that were collected for neonates maximum by 12 h after birth. Results It was found that patients with HIE had a statistically significant higher salivary LDH level (1927 ± 390.3 IU/L) than patients without HIE (523.6 ± 142.8 IU/L) (p < 0.001). Moreover, salivary LDH showed a good discriminative ability where the AUC was 0.966 regarding salivary LDH (95% CI: 0.917–1.0) (p < 0.001). The best cutoff value was 1420 IU/L or more which showed the best results in predicting the occurrence of HIE with 98.3% and 97.6% sensitivity and specificity, respectively. Conclusion Salivary LDH can be considered as a useful noninvasive laboratory marker that can accurately predict HIE incidence among neonates with asphyxia within 12 hours from birth. The cases in the HIE group were assigned into three stages according to the Sarnat and Sarnat staging system: stage I: mild (irritable, normal, or hypertonia and poor feeding); stage II: moderate (lethargy, hypotonia, and frequent seizure); stage III: severe (coma, flaccid, absent reflexes, and frequent seizure). There is a positive association between LDH levels and the severity of HIE.