Gills are the primary site of ionoregulation for most fishes. However, amphibious fishes experience diminished gill function during terrestrial sojourns due to a lack of water flow over the gills. Some amphibious species use cutaneous ionocytes for ion exchange. Previous work has shown an increase in the size and number of skin ionocytes during air-exposure in the amphibious mangrove rivulus (Kryptolebias marmoratus), presumably to maintain ion-balance. However, the factors regulating ionocyte remodelling during air-exposure were unknown. Using K. marmoratus as a model, and metyrapone as a pharmacological inhibitor of cortisol synthesis, we tested the hypothesis that cortisol regulates ionocyte remodeling and hydromineral balance during the transition of amphibious fishes from water to land. Our data show that the transition from water to air induces a rapid (within 5 minutes), robust (10-fold), and transient (maintained for the first 24 h in air, but subsequently return to resting levels by 7 days) increase in whole-body cortisol levels, and that exposure to metyrapone completely inhibits the rise in cortisol without impacting survival. We measured the morphometrics of skin ionocytes and found that a fish’s ability to mount a cortisol response significantly impacts their capacity for skin ionocyte remodeling. Following air-exposure, we also observed that a subset of skin ionocytes in each fish were of a novel morphology, with an irregular shape and multiple processes. Thus, cortisol plays a similar role in the skin of K. marmoratus as it does in the gills of fish moving from freshwater to seawater. Further studies are needed to determine if cortisol’s role in skin remodeling is universal in amphibious fishes.