Melon (Cucumas melon) is widely cultivated and popular because of its quality value and unique flavor. However, the continuous cropping of melons in greenhouses has various negative effects on the soil environment, melon growth, and quality. Recently, farmers have utilized organic fertilization, especially vermicompost, for melons to resist the harmful effects of continuous cropping. A field experiment was conducted to explore the effects of vermicompost on soil microbes and melon fruit quality via high throughput sequencing and chemical sequencing methods. The results showed that the application of vermicompost decreased (p < 0.05) soil pH and increased organic matter, available phosphorus, biomass, urease, catalase, peroxidase, and alkaline phosphatase. A total of 3447 bacterial and 718 fungal operational taxonomic units were identified in all soil samples. Application of vermicompost decreased (p < 0.05) the relative abundances of Acidobacteriota, Gemmatimonadota, Actinobacteriota, and unclassified and increased the relative abundance of Planctomycetota. Compared with the control soil, vermicompost application resulted in significantly higher bacterial Chao indices and a significantly lower Chao index under vermicompost of 60 t ha−1 based on farmers’ normal fertilizer and significantly lower diversity under vermicompost of 90 t ha−1. Otherwise, vermicompost application increased the photosynthetic rate and chlorophyll content of melon leaves and increased the total sugar, soluble solids, vitamin C, soluble protein, and organic acid contents of melon. The results of redundancy analysis indicated that Proteobacteria exhibited a positive correlation with soil ammonium nitrogen (AN) and pH, while showing a negative association with soil available phosphorus and organic matter. Spearman’s correlation analysis revealed that both total sugar content and central soluble solid content in melon had a significant positive correlation (p < 0.05) with Patescibacteria. This study demonstrates that the application of vermicompost alters the microbial community structure in melon cultivation, enhancing fruit quality; this not only promotes a healthier soil ecosystem but also contributes to sustainable and productive practices in melon farming.
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