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Introduction: Busulfan-related oxidative stress reduces fertility; therefore, this study aimed to investigate the protective role of crocin on ovarian histological changes. Materials & Methods: This study was conducted on 30 adult NMRI rats weighing 22-25 g in 6 equal groups in a 21-day period. The control group received a single dose (0.1 ml) of busulfan solvent (DMSO+PBS) intraperitoneally (IP) and the sham control group were subjected to a single dose of IP busulfan (10 mg/kg). Moreover, the experimental groups of 1, 2, and 3 received crocin intraperitoneally with doses of 100, 200, 400 mg/kg/day, respectively along with a single dose of busulfan (10 mg/kg). The positive control group received only crocin intraperitoneally at a dose of 400 mg/kg/day. After the end of the treatment period, animals were euthanized with a high-dose of ketamine. Left ovaries were used for the histomorphometric study. The data were analyzed using SPSS software (version19) through a one-way ANOVA and Bonferroni test. A P-value less than 0.05 were considered statistically significant. Ethics code: AECVU-192-2019 Findings: This study showed that the antioxidant properties of crocin could neutralize the busulfan-related oxidative stress which resulted in the growth of more healthy ovarian follicles and reduced the mean number of Atretic follicles, compared to the group received busulfan. Moreover, this study revealed dose-depended effects of crocin which indicated a significant benefit on the majority of parameters with a dose of 200 mg/kg. Discussion & Conclusions: The present study showed the remarkable ability of crocin in reducing the adverse effects of busulfan on the growth of ovarian follicles.