A new computational technique, the matched interface and boundary (MIB) method, is presented to model the photon propagation in biological tissue for the optical molecular imaging. Optical properties have significant differences in different organs of small animals, resulting in discontinuous coefficients in the diffusion equation model. Complex organ shape of small animal induces singularities of the geometric model as well. The MIB method is designed as a dimension splitting approach to decompose a multidimensional interface problem into one-dimensional ones. The methodology simplifies the topological relation near an interface and is able to handle discontinuous coefficients and complex interfaces with geometric singularities. In the present MIB method, both the interface jump condition and the photon flux jump conditions are rigorously enforced at the interface location by using only the lowest-order jump conditions. This solution near the interface is smoothly extended across the interface so that central finite difference schemes can be employed without the loss of accuracy. A wide range of numerical experiments are carried out to validate the proposed MIB method. The second-order convergence is maintained in all benchmark problems. The fourth-order convergence is also demonstrated for some three-dimensional problems. The robustness of the proposed method over the variable strength of the linear term of the diffusion equation is also examined. The performance of the present approach is compared with that of the standard finite element method. The numerical study indicates that the proposed method is a potentially efficient and robust approach for the optical molecular imaging.