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Soil microbiome is essential for promoting soil nutrient cycling, improving soil carbon sequestration, and maintaining soil fertility in agro-ecosystems. Red soil is an important cultivated land resource in southern China. However, it usually has the ecological problems of low soil organic matter content and severe soil erosion, including critical problems under soil acidification, such as increasing concentrations of active Fe and Al, which limit crop growth and decrease microbial activity. In recent years, many studies have been conducted based on long-term field experiments and short-term incubation experiments in red soil areas. Breakthroughs have been made in alleviating soil acidification, increasing soil organic matter content, and improving nitrogen and phosphorus availability by manipulating red soil microbiome. This brief review compared the effects of inorganic or/and organic fertilization on the structure and function of soil microbiome in upland red soil in southern China, and the main driving factors of soil microbiome structure in red soil were determined. Then, the positive effects of organic cultivations on the diversity of soil microbial communities were reviewed. The contributions of organic fertilizer-stimulated functional groups in promoting soil organic carbon decomposition and enhancing soil organic matter stability, including those of functional groups in triggering soil nitrogen and phosphorus metabolism, were summarized. The mechanism of the specialized metabolic functions embedded in high diversity microbial community driving soil microbiome assembly and stability was also discussed. Finally, this review proposed future developments in the study of agricultural red soil microbiome, emphasizing the importance of strategies for improving soil microbiome cultivation, clarifying the functional characteristics and driving factors of different soil microbial groups, exploring agro-microbiome resources, and consequently developing microbial fertilizer products and efficient agricultural managements for soil microbiome manipulation to improve the nutrient cycling efficiency, promote the stability of soil organic matter, and reduce the activity of iron and aluminum in red soil. These approaches will contribute to the sustainable utilization of red soil resources and the development of green agriculture.