Decline disease causes severe damage to bayberry. However, the cause of this disease remains unclear. Interestingly, our previous studies found that the disease severity is related with the level of soil fertilizer. This study aims to explore the effect and mechanism of compound fertilizer (CF) and bio-organic fertilizer (OF) in this disease by investigating the vegetative growth, fruit characters, soil property, rhizosphere microflora and metabolites. Results indicated that compared with the disease control, CF and OF exhibited differential effect in plant healthy and soil quality, together with the increase in relative abundance of Burkholderia and Mortierella, and the reduction in that of Rhizomicrobium and Acidibacter, Trichoderma, and Cladophialophora reduced. The relative abundance of Geminibasidium were increased by CF (251.79%) but reduced by OF (13.99%). In general, the composition of bacterial and fungal communities in rhizosphere soil was affected significantly at genus level by exchangeable calcium, available phosphorus, and exchangeable magnesium, while the former two variables had a greater influence in bacterial communities than fungal communities. Analysis of GC-MS metabonomics indicated that compared to the disease control, CF and OF significantly changed the contents of 31 and 45 metabolites, respectively, while both fertilizers changed C5-branched dibasic acid, galactose, and pyrimidine metabolic pathway. Furthermore, a significant correlation was observed at the phylum, order and genus levels between microbial groups and secondary metabolites of bayberry rhizosphere soil. In summary, the results provide a new way for rejuvenation of this diseased bayberry trees.