This paper reports the computed O2 binding to heme, which for the first time explains experimental enthalpies for this process of central importance to bioinorganic chemistry. All four spin states along the relaxed FeO2-binding curves were optimized using the full heme system with dispersion, thermodynamic, and scalar-relativistic corrections, applying several density functionals. When including all these physical terms, the experimental enthalpy of O2 binding (−59 kJ mol−1) is closely reproduced by TPSSh-D3 (−66 kJ mol−1). Dispersion changes the potential energy surfaces and leads to the correct electronic singlet and heptet states for bound and dissociated O2. The experimental activation enthalpy of dissociation (∼82 kJ mol−1) was also accurately computed (∼75 kJ mol−1) with an actual barrier height of ∼60 kJ mol−1 plus a vibrational component of ∼10 and ∼5 kJ mol−1 due to the spin-forbidden nature of the process, explaining the experimentally observed difference of ∼20 kJ mol−1 in enthalpies of binding and activation. Most importantly, the work shows how the nearly degenerate singlet and triplet states increase crossover probability up to ∼0.5 and accelerate binding by ∼100 times, explaining why the spin-forbidden binding of O2 to heme, so fundamental to higher life forms, is fast and reversible.