The brain and heart are two vital systems in health and disease, increasingly recognized as a complex, interdependent network with constant information flow in both directions. After severe traumatic brain injury (TBI), the causal, directed interactions between the brain, heart, and autonomic nervous system have not been well established. Novel methods are needed to probe unmeasured, potentially prognostic information in complex biological networks that are not revealed by traditional means. In this study, we examined potential bidirectional causality between intracranial pressure (ICP), mean arterial pressure (MAP), and heart rate (HR) and its relationship to mortality in a 24-h period early post-TBI. We applied Granger causality (GC) analysis to cardio-cerebral monitoring data from 171 severe TBI patients admitted to a single neurocritical care center over a 10-year period. There was significant bidirectional causality between ICP and MAP, MAP and HR, and ICP and HR in the majority of patients (p < 0.01). MAP influenced both ICP and HR to a greater extent (higher GC, p < 0. 00001), but there was no dominant unidirectional causality between ICP and HR (p = 0.85). Those who died had significantly lower GC for ICP causing MAP and HR causing ICP (p = 0.006 and p = 0.004, respectively) and were predictors of mortality independent of age, sex, and traditional intracranial variables (ICP, cerebral perfusion pressure, GCS, and pressure reactivity index). Examining the brain and heart with GC-based features for the first time in severe TBI patients has confirmed strong interdependence and reveals a significant relationship between select causality pairs and mortality. These results support the notion that impaired causal information flow between the cerebrovascular, autonomic, and cardiovascular systems are of central importance in severe TBI.