Cyclophosphamide (CTX) causes severe side effects on certain vital organs. Phoenix dactylifera seeds extract (PDSE) showed promising biomedical applications. This study aims to evaluate the phytochemical composition PDSE and its impact on CTX-induced hepato-renal toxicities in mice. The phytochemical compounds of PDSE were determined with gas-chromatography mass spectrometry (GC-MS). Forty male CD-1 albino mice were divided into four groups (n=10) as the following: Group 1 (Gp1) was served as a negative control. Gp2 was injected with PDSE (100 mg/kg) interperitoneally (i.p) daily for 30 days. Gp3 had injected with CTX (200 mg/kg) once, at day 0. Gp4 had injected with CTX/PDSE as in Gp3 and Gp2. Hematological, some biochemical parameters (Liver enzymes, kidney functions and antioxidant/oxidant biomarkers), histopathological alterations and gene expression for some pro-inflammatory cytokines in the liver and kidney tissues were assessed. GC-MS analysis showed that the 1-Heptatriacotanol and 9, 12, 15-Octadecatrienoic acid, 2, 3-dihydroxypropyl ester showed the highest peak areas (21.07 and 53.49%, respectively). The results showed that the treatment with PDSE for 30 days significantly ameliorated the hematological, biochemical, and histological alterations post CTX injection as evidenced by improving the liver/kidney functions, increasing the antioxidant enzymes, and down-regulating the tumor growth factor beta-1 (TGFβ-1), nuclear factor Kappa-beta (NFκ-β), cyclooxygenase-1 and 2 (COX-1 and 2) genes in both of the liver and kidney tissues. Furthermore, treatment with PDSE decreased the histopathological changes in the liver and kidney tissues that were induced by CTX-toxicity. Collectively, treatment with PDSE after CTX-injection showed potent ameliorating effect on both liver and kidney.