The outcomes of viral infections typically correlate with viral load in host tissues. In this study, we identified a H3N2 strain A/Environment/Guangxi/44461/2019 (GX19) that induced rapid mortality in mice by 4 days post-infection despite exhibiting low pulmonary replication capacity. Pathological analysis revealed that GX19 at 106 TCID50 (GX19-6) caused more severe lung damage than GX19 at 105 TCID50 (GX19-5), while inducing pulmonary pathology comparable to a H3N8 virus A/Changsha/1000/2022 at 106 TCID50 (CS-6). Both GX19-6 and CS-6 triggered greater cardiac damage than GX19-5. Notably, GX19-6 displayed unique neurovirulence, eliciting significantly more severe brain damage than GX19-5 and CS-6, accompanied by evident cerebral haemorrhage. Gene Set Variation Analysis (GSVA) revealed distinct cardiac gene expression profiles among viral infections. Specifically, GX19-5 up-regulated gene sets associated with arrhythmia, whereas GX19-6 triggered pathways involved in cardiac arrest. Neither of these effects was present in CS-6 infection. In the brain, GX19-6 specifically induced stronger upregulation of cerebral venous thrombosis and acute ischaemic stroke gene sets compared to other groups, consistent with its pronounced neuropathology. Transcriptomic profiling demonstrated significant alterations across all three organs in GX19-6-infected mice, showing suppression of T-cell immunity in the lungs and brain alongside elevated systemic inflammation. In the heart, increased inflammation and apoptosis were accompanied by impaired energy metabolism and reduced cardiac function, potentially contributing to the observed hypoxic responses in the heart, lungs, and brain. Collectively, these findings reveal an inflammation-driven lung-heart–brain axis in influenza virus pathogenicity.