The cis-1,1,1,4,4,4-hexafluoro-2-butene (DR-2 or HFO-1336mzz(Z)) is a novel environmentally friendly working fluid with appropriate physicochemical characteristics. The present work firstly investigates decomposition mechanism and thermal stability of DR-2 under the atmosphere containing oxygen (O2) and high temperature experimentally. The oxidative degradation features of DR-2 were explored at the temperature of 473-1073 K and the products were monitored by GC-MS and IC. The experimental and ReaxFF-based molecular dynamics results demonstrated the promotion effects of O2 on the DR-2 decomposition. The participation of O2 molecules was supposed to lower the initial thermal decomposition temperature by 240 K approximately and also would increase the number of products such as hydrogen fluoride (HF), but the enhancement effect was weakened by the increasing reaction temperature. The reasonable Arrhenius parameters calculated from the first-order kinetic analyses-based reactive molecular dynamics (RMD) simulations. Combined with density functional theory, the pathways of initial oxidation decomposition product firstly observed in the experimental and RMD simulations were proposed in this study. These results may pave the way for further study of DR-2 as a working fluid with lower global warming potential.