Cyclophosphamide (CP) is a well-known antineoplastic agent; however, its clinical use can be associated with various organ toxicities. Evening primrose oil (EPO) contains several phytoconstituents with potent anti-oxidant and anti-inflammatory activities. This experimental study was performed to investigate the chemoprotective effects of EPO in the liver and pancreas of CP-intoxicated mice. Thirty-two albino mice were randomly divided into 4 equal groups: group I received saline (control mice), group II were treated with CP at 100 mg/kg/day for two subsequent days, and groups III and VI were treated with 5 and 10 mg/kg/day bw EPO, respectively for 14 days, followed by two doses of CP at the 15th and 16th days of the experiment. Then, mice were sacrificed and histopathological examinations, biochemical studies, and DNA laddering tests were conducted for hepatic and pancreatic tissues. Cyclophosphamide-intoxicated mice showed significant increases (p < 0.05) in the serum levels of liver enzymes, pancreatic amylase and tissue levels of malondialdehyde, and TNF-α, as well as a significant decrease (p < 0.05) in the serum insulin level. In addition, both hepatic and pancreatic tissues showed disturbed tissue architecture, hydropic degeneration, congested vessels, and inflammatory infiltrates, as well as increased DNA fragmentation. In a dose-dependent manner, pretreatment with EPO was associated with significant improvements (p < 0.05) in all biochemical parameters and significant amelioration of histopathological alterations and DNA fragmentation in CP-intoxicated mice. Pretreatment with EPO showed significant antioxidant, anti-inflammatory, and genoprotective effects against the toxic effects of CP in mice hepatic and pancreatic tissues.