Heat stress (HS) is a primary environmental constraint threatening ruminant production, welfare and reproductive efficiency amid global warming. Current studies mostly focus on either systemic physiological damage or local ruminal dysfunction separately, while the bidirectional crosstalk between the rumen and host, as well as its amplifying effect on systemic pathology, remains to be systematically elucidated. This review integrates the latest evidence to construct a mechanistic framework centered on the neuro-endocrine-immune network, which acts as the core hub mediating rumen-host interactions under HS. Upon HS exposure, hyperactivation of the hypothalamic–pituitary–adrenal (HPA) and sympatho-adreno-medullary (SAM) axis drives systemic oxidative stress, immune dysfunction and chronic low-grade inflammation, disrupting whole-body homeostasis. Concurrently, HS reshapes the structure and functional profiles of rumen microbiota via three synergistic pathways: direct thermal sensing, host neuroendocrine regulation, and ruminal microenvironmental disturbance, thereby further impairing rumen fermentation homeostasis and epithelial barrier integrity, and triggering pathological endotoxin translocation. Critically, the neuro-endocrine-immune network transduces localized ruminal pathological signals into systemic metabolic and inflammatory disorders, and forms a self-perpetuating vicious cycle: systemic stress in turn aggravates ruminal ischemia, microbial dysbiosis and barrier damage, amplifying the initial pathological damage. By delineating this rumen-host pathological amplifier framework, this review provides targeted theoretical guidance for the development of multi-node intervention strategies to mitigate HS-associated production losses in ruminants.