Reasonable irrigation and fertilization practices can not only improve soil quality, but also increase crop yield, and water-fertilizer use efficiency. However, it is still unclear that the micro-irrigation and fertilization mode is conducive to improving the soil comprehensive environment, the mango yield and water-fertilizer use efficiency in the dry-hot region. The effects of regulated deficit irrigation (RDI) and fertilization levels on soil enzyme activity, soil microbial quantity, soil nutrient content, yield, water use efficiency (WUE) and partial fertilizer productivity (PFP) of mango in dry-hot region were studied. A randomized block design study with four irrigation levels [full irrigation throughout the growth period (FI), RDI during flowering (RDIFS), RDI during fruit expansion (RDIES), and RDI at maturity (RDIMS)] and three fertilization levels [FH, a water-soluble compound fertilizer (N:P2O5:K2O = 12:8:40) applied at 129.0 kg ha-1; FM, 103.2 kg ha-1; and FL, 77.4 kg ha- 1] was implemented in 2018 and 2019. The results showed that RDI reduced soil enzyme and microbial quantity, but increased nutrient content. With the decrease of fertilizer application rate, soil nitrate nitrogen, available phosphorus, available potassium content, urease, fungi and actinomycetes quantity decreased, while soil catalase, phosphatase activity and bacteria quantity increased first and then decreased. RDI reduced soil quality comprehensive index (SQI), and SQI decreased with the reduction of fertilization. Compared with FI, RDIFS and RDIES reduced mango yield and PFP, RDIFS reduced WUE, while RDIMS increased WUE and PFP. Compared with FH, FM increased mango yield, WUE and PFP, FL increased PFP. The yield, single fruit weight and PFP increased first and then decreased with the increase of SQI at different growth stages. RDIMSFM obtained the maximum mango yield and WUE. Thus, the treatment of regulated deficit irrigation at maturity stage and moderate fertilization (103.2 kg ha-1) was the suitable mode of water and fertilizer management for mango, which could realize water-saving and high yield of mango simultaneously in the dry-hot region of Southwest China.