To assess the accuracy of different quantum mechanical methods for biochemical modeling, the reaction energies of 20 small model reactions (chosen to represent chemical steps catalyzed by commonly studied enzymes) were calculated. The methods tested included several popular Density Functional Theory (DFT) functionals, second-order Møller Plesset perturbation theory (MP2) and its spin-component scaled variant (SCS-MP2), and coupled cluster singles and doubles and perturbative triples (CCSD(T)). Different basis sets were tested. CCSD(T)/aug-cc-pVTZ results for all 20 reactions were used to benchmark the other methods. It was found that MP2 and SCS-MP2 reaction energy calculation results are similar in quality to CCSD(T) (mean absolute error (MAE) of 1.2 and 1.3 kcal mol−1, respectively). MP2 calculations gave a large error in one case, and are more subject to basis set effects, so in general SCS-MP2 calculations are a good choice when CCSD(T) calculations are not feasible. Results with different DFT functionals were of reasonably good quality (MAEs of 2.5–5.1 kcal mol−1), whereas popular semi-empirical methods (AM1, PM3, SCC-DFTB) gave much larger errors (MAEs of 11.6–14.6 kcal mol−1). These results should be useful in guiding methodological choices and assessing the accuracy of QM/MM calculations on enzyme-catalyzed reactions.