Background: Inborn errors of metabolism (IEMs) are significant causes of illness and mortality, particularly in pediatric populations. Although each IEM is rare, their collective incidence is high. These genetic disorders often result in damage to the developing brain, leading to encephalopathy and other severe neurological symptoms. Aim: This study aimed to determine the incidence of IEMs in infants and children presenting with acute encephalopathy, developmental delay, psychomotor regression, or intractable seizures, using extended metabolic screening techniques. Patients and Methods: This prospective cohort observational study included 277 infants and children aged one month to fifteen years, presenting with the specified conditions. Patients were recruited from the inpatient wards, pediatric intensive care unit, and pediatric neurology outpatient clinic at Aswan University Hospital. Comprehensive clinical data were collected, and metabolic screening was performed using tandem mass spectrometry (MS/MS) and gas chromatography-mass spectrometry (GC/MS). Additional investigations included serum ammonia, lactate, random blood glucose, arterial blood gases, and neuroimaging studies. Results: Among the 277 patients, the mean age was 3.8 ± 3.42 years, with a slight male predominance (54.2%). Encephalopathy with or without developmental delay was the most common presentation (52.7%), followed by developmental delay (47.3%). Extended metabolic screening revealed abnormal results in 18.8% of patients. The most common metabolic disorders identified were glutaric acidemia (4.3%), fatty acid oxidation defects (3.2%), phenylketonuria (2.9%), and methylmalonic acidemia (2.5%). The metabolic group had higher rates of disturbed conscious levels (73.08%), hypotonia (34.62%), and hyporeflexia (26.92%). Elevated serum ammonia and lactate levels were significantly more common in the metabolic group. The study identified a statistically significant higher mortality rate in patients with abnormal metabolic screening results (13.46%) compared to those with normal results (1.78%). Conclusion: The study underscores the importance of comprehensive metabolic screening in pediatric patients presenting with encephalopathy, developmental delay, or intractable seizures. Early identification and appropriate management of IEMs are crucial for improving outcomes and preventing irreversible damage. The integration of advanced screening techniques such as MS/MS and GC/MS in routine clinical practice is essential for timely diagnosis and treatment.[