: Cisplatin is one of the most widely used anticancer drugs. As most of chemotherapeutic agents it doesn’t only target cancerous cells but also distributed to normal cells as well causing many organs toxicity. Being the most important organ in the immune system; the spleen affection by cisplatin treatment must be carefully prevented or reversed. This current study aimed to assess the protective effect of a Notch inhibitor dibenzazepine (DBZ) against cisplatin induced splenic toxicity as well as exploring the proposed mechanism shedding light to the role of Notch pathway in its effect. Methods: Rats were treated with DBZ (2mg/kg) for 12 days with a single dose cisplatin (7mg/kg) injected on 8th day of treatment. Rats were divided into four groups: Control, DBZ, Cisplatin and DBZ+ Cisplatin group. Results: Cisplatin injection upregulated the oxidative stress markers MDA and iNOS along with reduced antioxidant enzymes glutathione and catalase. The inflammatory markers (TNFα, IL1β and NK𝜅B) were also upregulated. Furthermore, the Notch-1 and Hes-1 expression were also significantly elevated. Cisplatin induced splenic tissue damage was further assured by light and electron microscopic histopathological examination. DBZ pre-treatment significantly restored the upregulated oxidative stress, inflammatory as well as Notch signaling pathways towards normal levels. Additionally, the histopathological architecture impairment was improved by Dibenzazepine. Conclusion: The study elucidated that DBZ protects against cisplatin-induced toxicity in rats via antioxidative and anti-inflammatory effects. Moreover, downregulating the Notch signaling pathway was proved to play a role in DBZ protective effect against cisplatin-induced splenic toxicity.