<p>Psychosocial stress in women is a major public health concern, yet the intergenerational mechanisms linking maternal premating stress to offspring neuropsychiatric vulnerability remain incompletely understood. Here, female mice were exposed to chronic unpredictable mild stress (CUMS) prior to mating, and offspring were assessed for neurodevelopment, adult behavior, and multi-omics profiles. Premating stress induced neurodevelopmental delays and sexually dimorphic adult phenotypes: female offspring exhibited hyperactivity and social deficits, whereas male offspring displayed anxiety. Cerebellum cytokine levels were reduced in a sex-dependent manner. Maternal stress shifted offspring gut microbiota (GM) composition, with <i>p_Proteobacteria</i> as core taxa in females and <i>p_Firmicutes</i> in males, exhibiting sex-dependent and inverse shifts in microbial network connectivity. Male offspring showed marked metabolic alterations and enhanced maternal–offspring metabolic concordance. Integrated analyses of GM, metabolites, and cerebellum profiles identified sexually dimorphic network correlations, further supported by human data demonstrating maternal stress-induced, sex-dependent GM network remodeling. Lactoferrin (LF) intervention selectively rescued male anxiety but not female behavioral deficits, and in males specifically, reduced cerebellum pro-inflammatory cytokines, enhanced GM network connectivity, and enriched immune-related serum metabolic and cerebellum transcriptomic pathways. LF also suppressed Purkinje cell firing frequency in males and reinforced post-treatment connectivity across microbial, metabolic, and cerebellum transcriptional nodes. Collectively, these findings delineate a previously unrecognized sexually dimorphic neuro–microbiota–metabolic network underpinning intergenerational vulnerability and highlight microbiota-targeted modulation as a systems-level mechanistic framework for sex-specific prevention of maternal stress–associated neuropsychiatric disorders.</p>