The present study was undertaken to assess the ability of ovarian hormones to alter methamphetamine (MA)-induced dopaminergic toxicity in male and female mice gonadectomized at 4 and 6 weeks of age. None of the following three treatments, estradiol benzoate (EB, 3 × 0.47 µg), progesterone (Prog, 3 × 0.47 µg), or EB (2 × 0.47 µg) followed by Prog (0.47 µg), affected the dopamine (DA)-depleting effects of MA in male and female mice gonadectomized when they were 4 weeks old. However, in contrast to the findings that male mice are more sensitive to MA-induced DA depletion than female mice, no sexual differences in the sensitivity to MA treatment were observed in mice gonadectomized at this age. Moreover, three daily doses of EB (0.47 µg) and EB (0.47 µg) combined with 4-hydroxytamoxifen (4OHT, 6 µg) effectively attenuated striatal DA depletion produced by MA in female mice ovariectomized at 6 weeks of age. Three daily doses of Prog (0.47 µg) and EB (0.47 µg) combined with 4OHT (6 µg) significantly attenuated MA-induced striatal DA depletion in male mice gonadectomized at 6 weeks of age. Taken together, the modulating effects of ovarian hormones on MA-induced DA depletion in mouse striatum could be sex- and age-dependent. 4OHT did not block the protecting effects of EB on MA-induced DA depletion in female and male mice, suggesting that the estrogen receptor may not be involved in the protective effects of EB on attenuating MA-induced DA toxicity.