The high-pressure equation of state (EOS) of energetic materials (EMs) is important for continuum and mesoscale models of detonation performance and initiation safety. Obtaining a high-fidelity EOS of the insensitive EM 1,3,5-triamino-2,4,6-trinitrobenzene (TATB) has proven to be difficult because of challenges in experimental characterization at high pressures (HPs). In this work, powder X-ray diffraction patterns were fitted using the recently discovered monoclinic I2/a phase above 4 GPa, which shows that TATB is less compressible than when indexed with the triclinic P1 phase. First-principles calculations were performed with Perdew−Burke−Ernzerhof (PBE) and PBE0 functionals including thermal effects using the P1 phase. PBE0 improves the description of hydrogen bonding and thus predicts accurate planar a and b lattice parameters under ambient conditions. However, discrepancies in the predicted lattice parameters above 4−10 GPa compared with experimental measurements indexed with P1 are further evidence of a structural modification at high pressure. Layer sliding defects are formed during molecular dynamics simulations, which induces an anharmonic effect on the thermal expansion of the c lattice parameter. In short, the results provide several insights into determining high-fidelity EOS parameters for TATB and other molecular crystals.