(C18H25NO, mole mass = 271) was investigated using thermal analyses (TA) measurements (TG/DTG and DSC) compared with EI mass spectral (MS) electron impact fragmentation at 70 eV of electron energy. Semi-empirical MO calculations using the PM-3 procedure were performed with dextromethorphan (DMP) as a neutral molecule and the corresponding positively charged ion. These included molecular geometry (bond length), bond order, bond strain, charge distribution on different atoms, heat of formation, and ionisation energy. The mass spectral fragmentation pathways and thermal analyses decomposition were proposed and compared with each other to select the most suitable scheme. In electron ionisation (EI) mass spectral fragmentation, the initial rupture is due to C3H7N (bridge) loss followed by C9H11O. In TA, the primary loss is due to loss of C3H7N Bridge + HBr (after H2O loss of crystallisation). TA revealed a high response of the drug to the temperature variation with very fast rate. It decomposed in several sequential steps in temperature range from 100oC to 600oC. The initial thermal decomposition was similar to that obtained using MS. So, it is possible to select the proper pathway using both techniques. This comparison was successfully confirmed by MO calculation. The structural reactivity effect on metabolism and the biological effect compared with codeine are discussed. .