Background: Cisplatin is one of the most widely used anticancer drugs. As with most of the chemotherapeutic agents, it doesn’t only target cancerous cells but is 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 explore the proposed mechanism shedding light on the role of the Notch pathway in its effect. Methods: Rats were treated with DBZ (2mg/kg) for 12 days with a single dose of cisplatin (7mg/kg) injected on the 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 expressions 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, and inflammatory as well as Notch signaling pathways toward normal levels. Additionally, the histopathological architecture impairment was improved by Dibenzazepine.