The knowledge about the effects of precipitation change and N deposition on soil microbe and enzymes is still limited for now. A field experiment was conducted with water- and N-addition treatments in a Chinese semi-arid grassland, and the dynamic changes of invertase, b-glucosidase, urease, dehydrogenase and substrate-induced respiration were monitored in 2011and 2012 to investigate the response of soil enzymes and microorganisms to increasing precipitation and N deposition. The results showed that the tested enzymes and substrate-induced respiration had significant intra- and inter-annual variations. The tested enzyme activities peaked at the beginning of the growing season in 2012, when the soil inorganic N was lower than that in 2011, but the substrate-induced respiration was not synchronous with the enzymes. Water addition had negative effect on the enzymes and substrate-induced respiration. N addition improved the activities of C-acquiring enzymes but decreased the activity of N-acquiring enzyme in the lower-precipitation year, while stimulated all four enzymes in the higher-precipitation year. There was a significant interaction between water addition and N addition on soil enzymes and microorganisms. This study highlighted that the inter-annual fluctuation of climates could be a non-ignorable interference to the effects of water and N treatments on soil extracellular enzymes and microorganisms.