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Depression involves dysregulation in distributed cortico-limbic networks, leading to behavioral deficits such as social avoidance. Ketamine is known for its rapid antidepressant effects. However, the complex multi-frequency interactions remain challenging, hindering systems-level understanding of depression and its treatment. Here, we present a frequency-varying multilayer brain functional network (FMBFN) analytical framework that characterizes brain-wide neural fluctuations and topological dimensions using in vivo local field potentials recording in eight regions and 16S RNA sequencing of gut microbiota. This approach quantifies multilayer topology to generate high-dimensional descriptors, enabling direct correlations with multimodal biological data and bridging neural activity with systemic domains. Applying the FMBFN framework, we show that chronic social defeat stress induces a pathological state of frequency-specific hyperconnectivity and disrupted global integration. Ketamine administration triggers a fundamental "network reset", characterized by global topological simplification and a dichotomous nodal reorganization—enhancing multilayer centrality in the lateral habenula while suppressing it in other regions. Finally, integration with gut microbiome data reveals bidirectional mediation between ketamine-altered bacteria and network reconfiguration, highlighting a functional gut-brain axis mechanism. In conclusion, the FMBFN framework provides a systems-level tool that bridges brain-wide functional architecture and gut microbiota, offering insights into psychiatric disorders and may inform future therapeutic strategies.