The modified DFTB3 Hamiltonian significantly improved the description of the hydride transfer reaction in Ccr, reproducing the reference DFT activation barrier within 0.1 kcal/mol and providing a qualitatively correct free energy profile. Moreover, we demonstrated the transferability of our approach by applying the new DFTB3 parameters to the hydride transfer reaction in DHFR, where it correctly reproduced the activation free energy barrier without further adjustments, and a small model system bearing the 1,4-dihydropyridine motif but with distinct structural features. This suggests that these parameters are likely transferable, particularly within the family of NAD(P)H-dependent oxidoreductases. Our work represents a significant step forward in the accurate and efficient modeling of hydride transfer reactions in enzymatic systems using more efficient semiempirical methods for extended sampling. We expect that the improved DFTB3 parametrization will enable more reliable QM/MM molecular dynamics simulations, potentially accelerating research in enzyme engineering, drug design, and the development of bio-inspired catalysts.