Combined application of humic acid (HA) and multi-nutrient fertilizer improve nutrient utilization and increase crop yield. To give insight about the application of HA compound fertilizer in sweet potato production, a field experiment was conducted the effect of humic acid-nitrogen, phosphorus, and potassium compound fertilizer (HA-NPK) on soil nutrient contents, soil enzyme activity, soil microorganism community structure and yield of sweet potato. Results showed that compared to nitrogen, phosphorus, and potassium compound fertilizer (NPK) treatment, the activated humic acid- nitrogen, phosphorus, and potassium compound fertilizer (HA-NPK1) and non-activated humic acid- nitrogen, phosphorus, and potassium compound fertilizer (HA-NPK2) treatment significantly increased the plant biomass and storage root yield. Increase in yield from application of HA-NPK1 was significantly larger than those from HA-NPK2. The HA-NPK1 treatment greatly increased the content of readily available phosphorus, potassium and soil organic matter, enhanced the enzyme activity of soil urease, invertase, alkaline phosphatase and catalase. The numbers of soil bacteria, fungi and actinomycetes in the HA-NPK1 treatment were significantly higher than the NPK treatment. In conclusion, the application of the activated HA-NPK in sweet potato production could be used effectively to increase soil quality, facilitate the growth of sweet potato and increase its yield under similar conditions to this work.