Traumatic brain injury (TBI) affects approximately 50% of the world population at some point in their lifetime. To date, there are no effective treatments as most of the damage occurs due to secondary effects through a variety of pathophysiological pathways. The phytoceutical curcumin has been traditionally used as a natural remedy for numerous conditions including diabetes, inflammatory diseases, and neurological and neurodegenerative disorders. We have carried out a system pharmacology study to identify potential targets of a difluorinated curcumin analogue (CDF) that overlap with those involved in the pathophysiological mechanisms of TBI. This resulted in identification of 312 targets which are mostly involved in G protein-coupled receptor activity and cellular signalling. These include adrenergic, serotonergic, opioid and cannabinoid receptor families, which have been implicated in regulation of pain, inflammation, mood, learning and cognition pathways. We conclude that further studies should be performed to validate curcumin as a potential novel treatment to ameliorate the effects of TBI.