The benzodiazepine midazolam (MDZ) is commonly used as first-line treatment in patients with acute seizures. This review summarizes the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of MDZ nasal spray (MDZ-NS), which can be administered by non–health care providers in the outpatient, ambulatory setting. Intranasal administration leads to rapid (t_max 9.0–21.5 min), consistent, and extensive absorption of MDZ, with fast distribution to the central nervous system (CNS), as demonstrated by the onset of sedation within 10 min after administration and the occurrence of peak psychomotor impairment at approximately 17–120 min after administration. Rapid plasma clearance of MDZ and its active metabolite 1-OH-MDZ (t_½ 3.6–8.1 h) results in a return to baseline alertness and psychomotor functionality by approximately 240 min post dose. The lack of first-pass metabolism reduces the potential for drug–drug interactions compared with oral dosing. Age (≥ 12 years), sex, race, body weight, body mass index, normal to moderately impaired renal function, and concomitant administration of cytochrome P450 (CYP)3A-inducing drugs are not considered important factors for MDZ-NS dosing. However, coadministration of MDZ-NS with moderate or strong CYP3A4 inhibitors should be avoided, and MDZ-NS should be used with caution when coadministered with mild CYP3A4 inhibitors, as these may result in prolonged MDZ effects owing to a decrease in plasma clearance. Taken together, the PK and PD properties of MDZ-NS, with a short t_max that translates into rapid CNS PD effects of sedation and psychomotor impairment, demonstrate rapid CNS penetration and onset of action, supporting its use for acute treatment of seizure clusters.