Background: Platinum compounds have been considered the 1st line drugs in the treatment of pediatric cancers despite their high organ toxicity. Conversely, Panax ginseng is known for its antioxidant, anti-inflammatory, and anti-stress properties. This study aimed to examine the histopathological and biochemical effects of cisplatin ± ginseng whole extract on hippocampal postnatal development, through investigation of oxidative stress, inflammatory, apoptotic pathways, effects on intracellular calcium homeostasis, and the subsequent effects on neurotransmitter levels. Methods: Rats’ offspring were allocated into four groups (Control group, Gin group (200 mg/kg orally from postnatal day (PD) 7, Cis group (single dose of 5 mg/kg, S.C at PD 10), and Gin/Cis group). At PD11 and PD17, male pups were weighed, tested for open field test then decapitated and hippocampal samples were prepared for both histological examination and tissue homogenate analysis Results: cisplatin significantly decreased BW and activity, histopathological changes (pyramidal and granular cells were fewer, shrunken, and deeply stained, with pyknotic nuclei and pericellular vacuolations), and a decrease in calbindin protein expression with immunohistochemistry. Additionally, Cis significantly increased oxidative stress (elevated MDA and decrease SOD levels), inflammatory, and apoptotic markers (TNF-α, IL-1β, and P53), but significantly decreased acetylcholine and GABA activity. All these alterations were more prominent on PD17 while prior/co-administration of ginseng provided considerable protection against such neurotoxic effects. Conclusion: wherefore there is no choice in using cisplatin as a chemotherapeutic agent, prior/co-administration of ginseng is recommended to alleviate the expected neurotoxic effect.