<p>Cytarabine (CTB), an antimetabolite anticancer drug, serves as cornerstone therapy for several blood cancers. Despite its exemplary efficacy, its use is associated with several toxic effects including developmental toxicity. Docosahexaenoic acid (DHA), a dietary omega-3 fatty acid, has demonstrated pleiotropic protective effects against various toxicities and is associated with improved pregnancy and neonatal outcomes and evidence suggests that DHA does not compromise, and may even enhance, the therapeutic effects of CTB. This study aimed to evaluate the protective effect of DHA against CTB-induced developmental toxicity in rat fetuses. Dams were divided into five groups and received the vehicle, DHA 200 mg/kg, CTB 12.5 mg/kg, CTB 25 mg/kg, and CTB 25 mg/kg plus DHA 200 mg/kg, respectively, from gestational day (GD)8 to GD14. The food intake and body weight of the dams were recorded daily. On GD15 blood samples were collected for hormonal assessment, and dams were sacrificed on GD21. CTB exposure during gestation resulted in a notable reduction in food intake, body weight gain, placental weight, estrogen, and progesterone levels, and elevation in oxidative stress markers in the placenta in dams. Prenatal CTB exposure led to fetal resorptions, fetal mortality, growth retardation, oxidative stress, and external developmental anomalies such as hematoma, phocomelia, oligodactyly, and impaired ossification in fetal axial and appendicular skeletal bones. Co-administration of DHA resulted in amelioration of the footprints of CTB-induced toxicity in pregnant rats as well as the fetus. These findings indicate that DHA has therapeutic potential against CTB-induced developmental toxicity. However, future experimental and clinical studies are warranted to explore the possible mechanisms involved in the protection offered by maternal supplementation of DHA against CTB-induced developmental toxicity.</p> Graphical Abstract <p></p>