Testing acclimation plasticity informs our understanding of organismal physiology and applies to conservation management amidst our rapidly changing climate. Although there is a wealth of research on the plasticity of thermal and hydric physiology in response to temperature acclimation, there is a comparative gap for research on acclimation to different hydric regimes, as well as the interaction between water and temperature. We sought to fill this gap by acclimating western fence lizards (Sceloporus occidentalis) to experimental climate conditions (crossed design of hot or cool, dry or humid) for 8 days, and measuring cutaneous evaporative water loss (CEWL), plasma osmolality, hematocrit and body mass before and after acclimation. CEWL changed plastically in response to the different climates, with lizards acclimated to hot humid conditions experiencing the greatest increase in CEWL. Change in CEWL among individuals was negatively related to treatment vapor pressure deficit and positively related to treatment water vapor pressure. Plasma osmolality, hematocrit and body mass all showed greater changes in response to temperature than to humidity or vapor pressure deficit. CEWL and plasma osmolality were positively related across treatment groups before acclimation and within treatment groups after acclimation, but the two variables showed different responses to acclimation, suggesting that they are interrelated but governed by different mechanisms. This study is among few that assess more than one metric of hydric physiology and that test the interactive effects of temperature and humidity. Such measurements will be essential for predictive models of activity and survival for animals under climate change.