The involvement of purinergic signaling in several brain functions has been recognized, but the modulation on maternal behavior by the purinergic system is not established, even though there are functional interactions between the purinergic and oxytocinergic systems. Therefore, the aim of our study was to investigate whether central administration of P2 receptor antagonists affected the maternal behavior of lactating rats and c-Fos immunoreactivity in the forebrain. On day 7 of lactation, female rats were treated with vehicle (5 μL; i.c.v.), suramin (9.4–75.0 μg/5 μL; i.c.v.) or PPADS (9.4–75.0 μg/5 μL; i.c.v.) 30 min before the experiment began. The maternal behavior was evaluated during the 30 min following suramin or PPADS administration. In addition, c-Fos-positive nuclei were counted in the medial preoptic area (MPOA) and in the bed nucleus of the stria terminalis (BNST), and neurons that were double-labeled for c-Fos/OT were counted in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus of lactating rats. The results show that P2 receptor antagonists decreased maternal care and decreased neuronal activation in the MPOA and BNST and activation of oxytocinergic neurons in hypothalamic nuclei. Our results indicate that the purinergic system modulates maternal behavior and neuronal activation induced by suckling during lactation.