Orphanin FQ/nociceptin (OFQ/N) inhibits the activity of proopiomelanocortin (POMC) neurons located in the hypothalamic arcuate nucleus (ARH) that regulate female sexual behavior and energy balance. We tested the hypothesis that estradiol modulates the ability of OFQ/N to pre- and postsynaptically decrease the excitability of these cells. To this end, whole-cell patch-clamp recordings were performed in hypothalamic slices prepared from ovariectomized rats, including some that were injected with the retrograde tracer Fluorogold in the medial preoptic nucleus (MPN) to label the POMC neurons regulating sexual receptivity. OFQ/N (1 µM) evoked a robust outward current in ARH neurons from vehicle-treated animals that was blocked by the opioid receptor-like (ORL)1 receptor antagonist UFP-101 (100 nM) and the G protein-gated, inwardly rectifying K⁺ (GIRK-1) channel blocker tertiapin (10 nM). OFQ/N also produced a decrease in the frequency of glutamatergic, miniature excitatory postsynaptic currents (mEPSCs), which was also antagonized by UFP-101. Estradiol benzoate (2 µg) increased basal mEPSC frequency and markedly diminished both the OFQ/N-induced activation of postsynaptic GIRK-1 channel currents and the presynaptic inhibition of glutamatergic neurotransmission. These effects were observed in identified POMC neurons, including eight that projected to the MPN. Taken together, these data reveal that estradiol attenuates the pleiotropic inhibitory actions of OFQ/N on POMC neurons: presynaptically through reducing the OFQ/N inhibition of glutamate release and postsynaptically by reducing ORL1 signaling through GIRK channels. As such, they impart critical insight into a mechanism for estradiol to increase the activity of POMC neurons that inhibit sexual receptivity.