Mephedrone (4‐methylmethcathinone) has been found in several over‐the‐counter products that are abused by humans, but very little is known about its behavioral effects and abuse liability. The present study examined the effects of mephedrone (1–10 mg/kg) on learning in female rats, as well as its interaction with the ovarian hormone estradiol. More specifically, female rats were trained to respond under a multiple schedule of repeated acquisition and performance of response sequences and then ovariectomized. Following ovariectomy, mephedrone dose‐effect curves were obtained during periods of 17β‐estradiol administration and periods without estradiol administration. Unlike mephedrone, which was administered acutely (i.p.) before the experimental sessions, 17β‐estradiol was administered via subcutaneous Silastic capsules containing 25% 17β‐estradiol and 75% cholesterol. In general, mephedrone produced dose‐dependent rate‐decreasing and error‐increasing effects in the acquisition and performance components of the schedule in all subjects. However, when estradiol was present, three of the four rats were more sensitive to the rate‐decreasing effects of mephedrone, and all of the subjects were more sensitive to its error‐increasing effects. These data indicate that estradiol can potentiate the disruptive effects of mephedrone on both the acquisition and performance of complex behavior in female rats.