Background: Pediatric poisonings from regulated pharmaceuticals and substances of abuse represent a severe global public health challenge. This study evaluated patterns, clinical manifestations, and outcomes of illicit drug exposures among pediatric patients admitted to Cairo University Children’s Hospital. Methods: This prospective observational study, conducted between January and December 2025, included 200 pediatric patients (<18 years). Cases were identified using a standardized clinical toxicology framework incorporating exposure history, toxidrome assessment, and qualitative urine immunoassay testing when available. Results: The cohort was predominantly male (65.5%, n=131) and primarily toddlers under 3 years of age (56.5%, n=113). All exposures occurred via ingestion (100%) within the home environment (100%), with 97.5% (n=195) determined to be unintentional. Cannabis was the most frequent exposure (64.0%, n=128), followed by regulated prescription medications: benzodiazepines (9.5%, n=19) and tramadol (9.0%, n=18). Nicotine and alcohol accounted for 6.0% (n=12) and 4.0% (n=8), respectively, while methamphetamine, pregabalin, and synthetic cannabinoids each accounted for 2.5% (n=5). Neurological depression was almost universal (99.5%, n=199), and convulsions were observed in 10.0% (n=20). Seventy-four percent of patients were admitted to the ICU primarily for continuous cardiorespiratory monitoring according to institutional policy. The overall survival rate was 99.0% (n=198). Two fatalities (1.0%) occurred, both following severe tramadol exposure. There was a statistically significant association between substance classes and vital sign derangements (p < 0.001). Conclusions: Toddlers within the domestic setting remain the highest risk group for accidental poisoning. While cannabis was the most prevalent exposure, the occurrence of two fatalities following tramadol ingestion serves as an important clinical safety signal.