AimThis study purposed to evaluate the modulator and protective role of Urtica dioica (UD) extract against deleterious effects of retinoic acid (RA) high doses on histological parameters and fertilization of rats.Materials and methodsFor the in-vivo phase, 60 female Wistar rats were divided into 6 identical groups as 1) control, 2) 25 mg/kg RA, 3) 25 mg/kg UD extract, 4) 50 mg/kg UD extract, 5) UD extract (25 mg/kg) + RA (25 mg/kg), and 6) UD extract (50 mg/kg) + RA (25 mg/kg). Biochemical parameters, including luteinizing hormone (LH), folliclestimulating hormone (FSH), malondialdehyde (MDA) levels, superoxide dismutase (SOD), and catalase (CAT) activities, were measured. In the in-vitro phase, oocytes were obtained from 10 female rats without injection. In addition to the mentioned parameters, histological parameters (oocytes in various stages) and the results of IVM, IVF, and embryo developments were assessed and compared among the groups with the use of one-way ANOVA and Tukey's post hoc tests.ResultsThe high dosage of RA significantly reduced the LH and FSH levels; however, UD alone and with RA increased the hormone levels in rats. Regarding the reactive oxygen species (ROS) activity levels in rats' blood samples, RA increased the MDA and decreased the SOD and CAT levels. Treatment with UD extract (UD + RA groups) significantly improved the parameters mentioned, showing UD's antioxidant effect. The rate of oocyte maturation, 2-cell–4-cell and 4-cell–8-cell embryos, and blastocyst formation increased significantly in the groups in which UD extracts were administered compared to the control and RA groups. Furthermore, the increases were significant in the UD + RA groups compared to the RA group.ConclusionUD extract can significantly reduce RA high doses side effects on histological parameters and fertilization of rats and has the protective potential against RA deleterious effects.