Persistent drought severely inhibits plant growth and productivity, which negatively affects terrestrial primary productivity worldwide. Therefore, it is important to investigate the impacts of drought on plant leaf CO 2 /H 2 O exchange and water use efficiency. This study assessed the responses of net photosynthesis (Pn), stomatal conductance (Gs), transpiration (Tr), and instantaneous water use efficiency (WUE) to drought based on a worldwide meta-analysis of 112 published studies. The results demonstrated that drought decreased Pn, Tr, and Gs significantly and differently among different moderators. C 4 plants had smaller Pn reduction than C 3 plants, which gives C 4 plants an advantage in Pn. But their WUE decreased under drought conditions, indicating a great flexibility in C 4 WUE. Annual herbs sacrificed WUE (−6.2%) to maintain efficient Pn. Perennial herbs took a different strategy in response to drought with an increased WUE (25.1%). Deciduous tree species displayed a greater increase in WUE than conifers and evergreen species. Additionally, Gs had a significant correlation with Pn and Tr, but an insignificant correlation with WUE, which could be because WUE is affected by other factors (e.g., air flow, CO 2 concentration, and relative humidity). These findings have significant implications for understanding the worldwide effects of drought on plant leaf CO 2 /H 2 O exchange and water use efficiency.