Neonatal hypoxia-ischemia (HI), restricted oxygenation and reduced cerebral bloodflow to the brain is a significant cause of neonatal morbidity and mortality. Therapeutic Hypothermia (TH) is the only licensed treatment for HI, however, 40% of TH-treated neonates still develop neurodevelopmental disabilities. Curcumin induces powerful antioxidant activity, with evidence of significant neuroprotection in a neonatal HI mouse model. However, curcumin has limited therapeutic usage due to poor bioavailability and aqueous insolubility. This study aimed to: i) compare free synthetic vs natural curcumin neuroprotection in vivo and i) improve curcumin bioavailability through nanoformulation synthesis.In a neonatal HI mouse model in vivo therapeutic efficacy was assessed with: a behavioural assay (negative geotaxis) determining motor coordination, and histological analyses assessing levels of glial activation and cell death. Natural and synthetic nanoformulations in conjunction with other agents were assessed in vitro for their pharmaceutical properties (antioxidant assay and laser diffraction) and their cytotoxicity (cell viability). [MH1]This study’s in vivo results showed that the neuroprotective effects of synthetic/natural curcumin in an HI mouse model displayed a (insignificant) reduction of glial activation compared to untreated controls. Results showed that the pharmaceutic properties of synthetic and natural curcumin formulations have negligible differences, and possess promising properties with significant antioxidant activity, and optimal nanoparticle size (<100nm) and surface potential (>±10mV). Novel nanoformulations presented adequate cell viability (>50%), with adjuncts improving viability significantly. In conclusion, future in vivo application of this study’s nanocarrier formulations may indicate potential significant therapeutic efficacy in comparison to free curcumin alone.