Kinetic analysis for the non-isothermal decomposition of un-irradiated and photon-beam-irradiated 5-fluorouracil (5-FU) as anti-cancer drug, was carried out in static air. Thermal decomposition of 5-FUproceeds in two steps. One minor step in the temperature range of (270–283◦C) followed by the majorstep in the temperature range of (285–360◦C). The non-isothermal data for un-irradiated and photon-irradiated 5-FU were analyzed using linear (Tang) and non-linear (Vyazovkin) isoconversional methods.The results of the application of these free models on the present kinetic data showed quite a dependenceof the activation energy on the extent of conversion. For un-irradiated 5-FU, the non-isothermal dataanalysis indicates that the decomposition is generally described by A3 and A4 modeles for the minor andmajor decomposition steps, respectively. For a photon-irradiated sample of 5-FU with total absorbed doseof 10 Gy, the decomposition is controlled by A2 model throughout the coversion range. The activationenergies calculated in case of photon-irradiated 5-FU were found to be lower compared to the valuesobtained from the thermal decomposition of the un-irradiated sample probably due to the formation ofadditional nucleation sites created by a photon-irradiation.The decomposition path was investigated by intrinsic reaction coordinate (IRC) at the B3LYP/6-311++G(d,p) level of DFT. Two transition states were involved in the process by homolytic rupture ofN H bond and ring secession, respectively.