Background: Trigemino-cardiac reflex is a unique brain stem reflex that manifests as negative cardio-respiratory perturbations. This reflex is largely reported in skull base surgeries/interventions; however, in recent times, it has been also linked with many neurosurgical, neurointerventional procedures, non-neurosurgical and non-surgical conditions. This reflex presents with many cardiovascular changes that can create catastrophic complications, worse outcome as well as diagnostic dilemmas. Therefore, this narrative review intends to elaborate on its mechanisms, definition, pathophysiology, manifestations, diagnosis and management.