Doxazosin (C23H25N5O5) is α1-selective alpha blocker used to treat high blood pressure and urinary retention associated with benign prostatic hyperplasia (BPH). The doxazosin (DOX) drug was investigated using electron impact mass spectral (MS) fragmentation at 70 and 15 eV of electron energy, thermal analysis (TA) measurements and confirmed by molecular orbital calculations using density functional theory(DFT) calculations and natural bond orbital (NBO) analysis. The mass spectra and thermal analysis fragmentation pathways were proposed and compared to each other to select the most suitable scheme representing the correct fragmentation pathway of the drug in both techniques. The optimum molecular geometry and the total energy of the neutral and the positively charged DOX molecules were calculated by density functional theory method with 6-311G basis sets and natural bond orbitals (NBO) analysis. The molecular orbital calculations provides a base for fine distinction among sites of initial bond cleavage and subsequent fragmentation of drug molecule in both TA and MS techniques; consequently the choice of the correct pathway of such fragmentation knowing this structural session of bonds can be used to decide the active sites of this drug responsible for its chemical, biological and medical reactivity.