Abstract: Desert karst habitats are an important factor restricting the growth of karst plants. High temperature and drought stress caused by extreme climatic events bring new challenges to the adaptation of karst moss plants to environmental changes. In this study, we simulated high temperature and drought stress experiments to investigate the physiological changes and adaptability of epilithic moss (Homomallium simlaense (Mitt.) Broth. Mitt) under stress conditions in the karst environment. Results showed that the physiological and biochemical indices of H. simlaense exhibited significant positive correlations with the relative water content in plants under high temperature and drought treatment. The MDA, osmotic adjustment substances, and chlorophyll content decreased with decreasing moss water content and with increasing temperature and drought treatment duration. However, H. simlaense maintained a higher soluble sugar concentration to maintain the balance of osmotic pressure. In addition, H. simlaense also survived extreme drought and high temperature stress by decreasing physiological activity and maintaining soluble sugar content within a certain range. At the same time, the MDA content was at the lowest level. Restoring water after drought, the osmotic adjustment substances and MDA contents were higher than that of plants under continual high temperature and drought stress, and the photosynthetic capacity also recovered rapidly. Results suggested that the adaptation of H. simlaense to drought and high temperature may be closely related to increasing MDA content. Thus, H. simlaense showed resistance to high temperature and drought stress partly due to its long-term residence in harsh karst environments.