To verify an effective approach for alleviating problems associated with the consecutive monoculture of sweet potato, five fertilizer treatments were designed under plastic film-mulched, drip-fertigated conditions in fields continuously planted with sweet potato over five years. These treatments included: (1) no fertilizer application, (2) basic application of water-soluble (WS) fertilizer, (3) basic application of biofertilizer (BF) and WS fertilizer, (4) split application of WS fertilizer, and (5) combined basic application of BF and split application of WS fertilizer. The effects of BF and WS fertilizer applications on yield, quality, and soil properties were evaluated. Fertilizer applications had positive effects on increasing soil activities and nutrients compared with no fertilizer application. Split fertigation with WS fertilizer increased the activities of soil dehydrogenase (DHA) by 10.94 ~ 14.74%, alkaline phosphatase (ALP) by 4.97 ~ 5.13%, and soil organic matter (SOM) by 10.43 ~ 12.47% in the second year compared with a single application. In both years, split fertigation exerted positive effects on increasing dry matter (DM) accumulation in tuberous roots and increased the productive efficiency in nitrogen (N), phosphorus (P), and potassium (K) fertilizers. BF application for two consecutive years increased the activities of soil sucrase by 7.05 ~ 17.83%, DHA by 18.65 ~ 21.34%, ALP by 6.87 ~ 7.03%, soil available P by 18.34 ~ 28.10%, and SOM by 8.18 ~ 10.17% compared with the no BF application. BF also increased the root yield by 8.88 ~ 14.14%, the carotenoid content in tuberous roots by 20.38 ~ 30.64%, and the K utilization efficiency by 11.09 ~ 14.97%. The combination of BF and split fertigation for two consecutive years was most conducive to the activation of soil nutrients, maintenance of soil fertility, and improvement in yield and quality, which could mitigate problems associated with the consecutive monoculture of sweet potato.