Repeated or prolonged use of general anesthetics in pregnant women may disturb the neurodevelopment of infants. Compelling evidence indicates that maternal exercise during pregnancy has positive effects on the cognitive function of offspring. We previously confirmed the preventive potential of maternal treadmill training for cognitive deficits induced by in utero exposure to sevoflurane in rat pups. However, the underlying mechanism(s) needed further clarification. Thus, the aim of the present study was to investigate the effects of maternal exercise on the epigenetic regulation of genes linked to brain plasticity and function. Pregnant rats on gestational day 13 (GD 13) received 2 h of 3% sevoflurane or 30% oxygen daily on three consecutive days (GD 13-15). Pregnant rats in the exercise groups were forced to run on a treadmill for 60 min/day, 5 days/week, for a duration of 3 weeks. On postnatal day 0 (PND 0), the brains of rat pups were harvested for biochemical and histochemical studies. On PNDs 28-33, the learning and memory ability of rat pups was assessed using Morris water maze task. Maternal exercise ameliorated sevoflurane-induced decreases in p300 histone acetyltransferase (HAT) expression and inhibition of BDNF signaling. Maternal exercise improved performance in the Morris water maze task. However, these effects were reversed by p300 inhibitor. Our results indicated that maternal treadmill exercise during pregnancy can ameliorate cognitive dysfunction induced by prenatal sevoflurane exposure; p300 HAT-mediated BDNF signaling activation might contribute to the neuroprotective effects of maternal exercise.