PURPOSE. Intraocular pressure (IOP) remains the only modifiable risk factor for glaucoma progression. Our previous discovery that stimulation of nuclei within the hypothalamus can modulate IOP, intracranial pressure (ICP), and translaminar pressure difference (TLPD) fluctuations led us to investigate this pathway further. Our purpose was to determine the role of orexin neurons, primarily located in the dorsomedial hypothalamus (DMH) and perifornical (PeF) regions of the hypothalamus, in modulating these pressures. METHODS. Sprague Dawley rats were pretreated systemically with a dual orexin receptor antagonist (DORA-12) at 30 mg/Kg (n = 8), 10 mg/Kg (n = 8), or vehicle control (n = 8). The IOP, ICP, heart rate (HR), and mean arterial pressure (MAP) were recorded prior to and following excitation of the DMH/PeF using microinjection of the gamma-aminobutyric acid (GABA)A receptor antagonist bicuculline methiodide (BMI). RESULTS. Administration of the DORA at 30 mg/Kg significantly attenuated peak IOP by 5.2 ± 3.6 mm Hg (P = 0.007). During the peak response period (8-40 minutes), the area under the curve (AUC) for the 30 mg/Kg DORA cohort was significantly lower than the control cohort during the same period (P = 0.04). IOP responses for peak AUC versus DORA dose, from 0 to 30 mg/Kg, were linear (R2 = 0.18, P = 0.04). The ICP responses during the peak response period (4-16 minutes) versus DORA dose were also linear (R2 = 0.24, P = 0.014). Pretreatment with DORA significantly decreased AUC for the TLPD following stimulation of the DMH/PeF (10 mg/kg, P = 0.045 and 30 mg/kg, P = 0.015). CONCLUSIONS. DORAs have the potential to attenuate asynchronous changes in IOP and in ICP and to lessen the extent of TLPDs that may result from central nervous system (CNS) activation.