Noise can induce hearing loss. In particular, noise can induce cochlear synapse degeneration leading to hidden hearing loss, which is the most common type of hearing disorders in the clinic. Currently, there is no pharmacological treatment, especially no post-exposure (i.e., therapeutic) treatment available in the clinic. Here, we report that systemic administration of K(+) channel blockers by intraperitoneal injection before or after noise exposure significantly ameliorated noise-induced hearing loss (NIHL) and cochlear synapse degeneration. After systemic administration of a general K(+)-channel blocker tetraethylammonium (TEA) before or after noise exposure, the noise-induced threshold elevation of auditory brainstem responses (ABRs) and reduction of suprathreshold responses were significantly attenuated. The impairment on the active cochlear mechanics measured by distortion product otoacoustic emission (DPOAE) was also reduced. The therapeutic effect was further improved as the post-exposure administration time extended. BK channel is a predominant K(+) channel in the inner hair cell. We further found that post-exposure administration of a BK channel blocker GAL-021 could ameliorate NIHL and improved the hearing behavioral responses examined by acoustic startle response (ASR). Finally, both TEA and GAL-021 significantly reduced noise-induced ribbon synapse degeneration. These findings demonstrate a promise of systemic administration of K(+) channel blockers to treat synapse degeneration and NIHL after noise exposure, which currently is urgently required in the clinic.