Hemorrhagic shock, caused by trauma, is a leading cause of preventable death. A combination treatment of d-β-hydroxybutyrate (BHB) and melatonin (MLT), in dimethyl sulfoxide - water, increased survival. A freeze-dried BHB–MLT formulation, with a short reconstitution time, has been developed. This intravenous formulation, prepared with an aqueous vehicle, completely eliminated dimethyl sulfoxide, thereby avoiding the potential problems associated with this solvent. The poor aqueous solubility of MLT necessitated the use of polyvinylpyrrolidine (PVP) as a complexing agent. Thus the prelyophilization solution contained BHB (2 M), MLT (21.5 mM) and PVP (40 mM). Using a combination of low-temperature X-ray diffractometry and thermal analysis, the lyophilization process parameters were optimized. Infra-red spectra revealed hydrogen bonding interaction between PVP and MLT, while BHB crystallized as BHB.0.25 H2O in the final lyophile. The formulation improved survival in a rat model of hemorrhagic shock. Based on the increase in rate of survival and longer survival time compared to untreated animals, we conclude that this formulation can serve as a promising first line of treatment for hemorrhagic shock.