In this paper, the first-principles method based on density functional theory and non-equilibrium Green’s function is used to investigate the modulation of quantum interference and spin transport in N and B atom substituted meta-phenylene (M-OPE) molecular devices. The zero bias spin transmission spectrum of M-OPE molecular device shows that highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) are located at higher energy positions on both sides of the Fermi level, and there is a clear transmission spectrum valley (anti resonance peak) on the right side of the Fermi level. This indicates that M-OPE molecules are typical destructive quantum interference molecular systems. Research has found that N and B atoms replace carbon atoms at positions 1, 2, and 3 on the central ring of the molecule, which suppress the original destructive quantum interference of M-OPE molecular device to different extents. The substitution of N and B atoms at position 1 has no effect on the original destructive quantum interference of M-OPE molecular device, while the substitution of N and B atoms at positions 2 and 3 significantly suppresses the original destructive quantum interference of M-OPE molecular device. Therefore, there is a significant difference in the electrical conductivity of devices with N and B atoms at different positions, with the order of electrical conductivity values being N2 > N3 > N1 and B2 > B3 > B1. In this study, it is also found that the spin current value of device with B atom substitution is significantly higher than that of device with N atom substitution. After the substitution of B atom at position 2, the spin current value of the device under negative bias is significantly greater than that under positive bias, exhibiting a significant spin rectification effect. Based on the extended curled arrow rule proposed by O’Driscoll et al. to predict the behavior of quantum interference effects, we explain the physical mechanism by which N and B protons at different positions have different effects on the suppression of quantum interference in M-OPE molecular device. The results of the quantum interference and spin transport regulation of molecular systems by the substitution of B and N atoms can provide theoretical guidance for realizing the further application of heterocyclic aromatic hydrocarbons in molecular electronics.