To alleviate the continuous cropping obstacle in the main sweet potato production areas of Hunan Province, the typical acid soil continuous cropping obstacle land in Hunan Province was selected as the test area and ‘Xiangshu 203’ was selected as the test variety. Three fertilizer factor treatments of special compound fertilizer for sweet potato, microbial fertilizer, and organic fertilizer were set up. For each individual factor, four fertilization levels of 0.0 times, 0.5 times, 1.0 times, and 2.0 times the recommended fertilization amount were set up, respectively. Single-fertilizer experiments and L16(43) orthogonal fertilizer combined application tests were carried out to compare and analyze the differences in fresh sweet potato yield, dry matter accumulation, soil nutrients, and economic benefits in each test area. The results showed that in the single fertilizer test, the special compound fertilizer produced the highest sweet potato yield, followed by organic fertilizer, while microbial fertilizer demonstrated the lowest yield increase. Applying 600 kg/hm2 of special compound fertilizer yielded 28.17 t/hm2 of the actual fresh sweet potato, and the yields of the plots treated with organic fertilizer and microbial fertilizer at the same nutrient-equivalent application rate were close to this level. In the mixed-fertilizer orthogonal tests, the combining organic and compound fertilizers at an equal fertilizer-efficiency ratio produced the greatest yield increase. The highest fresh sweet potato yield(36.25 t/hm2) occurred with 1 500 kg/hm2 of organic fertilizer plus 600 kg/hm2 of special compound fertilizer, exceeding the 300 kg/hm2 of special compound fertilizer+750 kg/hm2 of organic fertilizer treatment by 22.43%, and the individual applications of special compound fertilizer and organic fertilizer by 28.69% and 31.87%, respectively. In the single-fertilizer tests, the dry matter accumulations of the three fertilizers peaked under the recommended fertilization amounts. In the fertilizer mixed application tests, the dry matter accumulation peaked under the treatment of 600 kg/hm2 of special compound fertilizer+750 kg/hm2 of microbial fertilizer+3 000 kg/hm2 of organic fertilizer. Fertilization had a great influence on soil nutrient contents, mainly manifested as special compound fertilizer significantly increased soil available nutrient contents, organic fertilizer significantly increased soil organic matter content, but microbial fertilizer had little influence on soil nutrient contents. The greatest economic return(20 620 yuan/hm2) was achieved with 600 kg/hm2 of special compound fertilizer+1 500 kg/hm2 of organic fertilizer. In conclusion, the relatively optimal fertilization strategy to alleviate continuous cropping obstacles was 600 kg/hm2 of special compound fertilizer+1 500 kg/hm2 of organic fertilizer.