The reactivity of prednisolone (Pd) to gamma radiation in aqueous and organic solutions has been investigated using Cobalt 60 source in a Gammacell-220 and radiation doses of 0.25, 0.5, 1.0, 2.0, 3.0, 4.5, 6 and 9 KGy. The residual drug concentration was determined by HPLC method using 45:55 acetonitrile: water as mobile phase on a reversed phase column and UV detector at 254 nm. The degradation kinetics study showed an initial zero-order followed by complex reactions illustrated graphically as an overall first order kinetic. The study revealed that the drug was significantly more sensitive to gamma radiation in aqueous solutions than organic solvents, with degradation rates of 1.34 and 0.67 × 10 − 4 M/KGy for aqueous and propylene glycol solutions, respectively. The structure activity relationship of the organic solvents (ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tertiary butanol, 1-3 propane-diol, propylene glycol and glycerin), as pure solvents has been studied. Although the difference was not significant, the alkyl chain length and branching increased the reactivity of the solvent to radiation. Moreover, the number and position of hydroxyl groups in the solvent structure have significantly increased its sensitivity to radiation which has been manifested as increased drug degradation. Isoropanol and tertiary butanol as free radical scavengers have shown variable protective effects for the drug against radiation. The role of different types of surfactants (sodium lauryl sulfate, Tween 80 and benzalkonium chloride) in drug protection against radiation in aqueous solutions suggested two different mechanisms. The first is the scavenging effect of the surfactant monomers below its CMC. Above CMC, a second mechanism may be involved, where the drug is expected to be located inside the formed micelles to different extents according to its affinity to the surfactant leading to more stabilization of the drug. The protective effect of surfactants was found to be in the order: sodium lauryl sulfate > Tween 80 ≥ benzalkonium chloride.