Organic manure is widely applied in agricultural systems to improve soil nutrient cycling and other physicochemical properties. However, the biotic and abiotic mechanisms that drive C, N, P, and S cycling following manure application are not completely understood. In this study, soil samples were collected from long-term experimental plots that had been amended with farmyard manure or mineral fertilisers since 1964. Isotope labelling with 15N, 33P, and 35S; metagenomics; and high-throughput sequencing were used to reveal the relationships between C, N, P, and S dynamics and microbial community composition and functions depending on fertilisation. A clear niche differentiation was observed between bacteria and fungi under mineral and manure regimes. A network analysis showed that long-term manure application reduced the complexity and stability of soil microbial network. Furthermore, a variation partitioning analysis based on redundancy analysis indicated that microbial community variation was mainly driven by soil Cand N contents. Dissolved organic C was the most important factor regulating microbial community structure. Soil C and N contents explained 43.5% of bacterial and 37.9% of fungal community variations. In contrast, soil P and S contents explained 29.9% of bacterial and 20.3% of fungal community variations. Long-term manure application increased the abundance of most functional genes related to C, N, P, and S cycling. This led to increased C and N cycling rates under manure application, which provided sufficient substrates for microbial growth. Partial least squares path modelling indicated that soil physicochemical properties, especially dissolved organic carbon, directly influenced C and S cycling, whereas the N and P cycles were indirectly affected by the changes in microbial community composition. These results provide a new perspective on both direct and indirect effects of organic manure and inorganic fertilisers on the soil nutrient cycling processes mediated by soil microbial community.