The thermal oxidation of two potential extractants for minor actinides in nuclear fuel reprocessing was investigated. These extractants were N,N′-dimethyl, N,N′-dibutyl, tetradecyl malonamide (DMDBTDMA), used as a model, and N,N′-dimethyl, N,N′-dibutyl, dodecylethoxy malonamide (DMDBDDEMA), used as a modified structure. An experimental methodology with two factorial designs was used to quantify the influence of different factors. In the first design, the factors were reaction time, temperature and oxidant type for experiments carried out on a pure solution of DMDBTDMA. The influence of temperature was clearly shown in the range of 200–250 °C. In the second design, the temperature was fixed at 250 °C, the humidity factor was introduced and experiments were carried out on a 0.5 mol l−1 solution of DMDBTDMA in n-dodecane, which represents the extractant concentration in nuclear fuel waste processing. This second series confirmed the efficiency of oxygen for destroying diamides. The results of thermal destruction were also compared with data photo-oxidation. Coupled experiments were also performed combining first photo-oxidation and secondly thermal oxidation with oxygen. This combination destroyed more than 99% of initial diamides.