Noise is the most common occupational and environmental hazard. Noise-induced hearing loss (NIHL) is the second most common form of sensorineural hearing deficit, after age-related hearing loss (presbycusis). Although promising approaches have been identified for reducing NIHL, currently there are no effective medications to prevent NIHL. Development of an efficacious treatment has been hampered by the complex array of cellular and molecular pathways involved in NIHL. We turned this difficulty into an advantage by asking whether NIHL could be effectively prevented by targeting multiple signaling pathways with a combination of drugs already approved by U.S. Food and Drug Administration (FDA). We previously found that antiepileptic drugs blocking T-type calcium channels had both prophylactic and therapeutic effects for NIHL. NIHL can also be reduced by an up-regulation of glucocorticoid (GC) signaling pathways. Based on these findings, we tested a combination therapy for NIHL that included ethosuximide and zonisamide (anticonvulsants) and dexamethasone and methylprednisolone (synthetic GCs) in mice under exposure conditions typically associated with dramatic permanent threshold shifts (PTS). We first examined possible prophylactic effects for each drug when administered alone 2h before noise, and calculated the median effective dose (ED50). We then tested for synergistic effects of two-drug combinations (anticonvulsant+GC), and identified combinations with the strongest synergy against NIHL, based on a previously established combination index (CI) metric. We repeated similar tests to determine their therapeutic effects when administered the same drugs 24h after the noise exposure. Our study shows the feasibility of developing pharmacological intervention in multiple pathways, and discovering drug combinations with optimal synergistic effects in preventing permanent NIHL.