Cytochrome P450 monooxygenases (P450s) are well recognized as versatile bio-oxidation catalysts. However, the catalytic functions of P450s are highly dependent on NAD(P)H and the redox partner proteins. Our group has recently reported to use a dual-functional small molecule (DFSM) for generating peroxygenase activity of P450BM3, a long-chain fatty acid hydroxylase from Bacillus megaterium. The DFSM-facilitated P450BM3 peroxygenase system exhibited excellent peroxygenation activity and regio-/enantioselectivity for various of organic substrates, such as styrenes, thioanisole, small alkanes, and alkylbenzenes. Very recently, we demonstrated that the DFSM-facilitated P450BM3 peroxygenase could be switched to a peroxidase by engineering the redox-sensitive tyrosine residues in P450BM3. Given the great potentials of P450 peroxidase for C-H oxyfunctionalization, we herein report to scrutinize the effect of mutating redox-sensitive residue on peroxidase activity by deeply screening all redox-sensitive residues of P450BM3, such as Methionines, Tryptophans, Cysteines, and Phenylalanines. As a result, six beneficial mutations at positions of M212, F81, M112, F173, M177, and F77 were screened out from 78 constructed mutants, which significantly enhanced the peroxidase activity of P450BM3 in the presence of Im-C6-Phe, a typical DFSM molecule. Further combination of the beneficial mutations resulted in more than 100-fold improvement of peroxidase activity compared with that of the combination of parent enzyme and DFSM, comparable to or better than most natural peroxidases. In addition, mutations of redox-sensitive residues even dramatically increased more than 300-fold peroxidase activity of the start F87A enzyme in the absence of DFSM, despite far lower apparent catalytic turnover number compared with the DFSM-P450 system. This study provides new insights and potential strategy for regulating catalytic promiscuity of P450 enzymes for multiple functional oxidations.