Non-polio enteroviruses (NPEVs) are a known cause of neurological illnesses, and in recent years, respiratory complications have been linked to EV-D68, EV-A71, and human rhinovirus (HRV). Understanding and identifying the molecules responsible for the inflammatory responses associated with NPEVs is vital to targeting current therapeutic compounds effectively. One such molecule is HMGB1, which plays a critical role in inducing inflammation. Disulfide-HMGB1 interaction with TLR-4 leads to the release of pro-inflammatory cytokines. Infected or dying cells also secrete extracellular HMGB1 and innate immune molecules. The HMGB1-RAGE axis can trigger inflammasome formation by activating caspase-1, resulting in pyroptosis. Recent research has shown that EV-A71 infection induces gasdermin-D, which causes perforations in the plasma membrane and subsequent inflammasome formation and causes pyroptosis. This cascade releases IL-1β and IL-18, leading to cell lysis, inflammatory cell recruitment, and increased cytokine production. However, excessive production of these cells and cytokines can lead to severe complications, including cytokine storms that exacerbate disease symptoms. By focusing on these key molecular targets and pathways, we can move further to mitigate the devastating effects of uncontrolled inflammation during viral infections, including NPEVs. The therapeutic potential of compounds such as HMGB1 inhibitors, P2X7 receptor antagonists, and anti-inflammatory agents like ethyl pyruvate, heparin, glycyrrhizin, and resveratrol offers exciting avenues for future research and clinical application.