For fluorescence tomographic imaging of small animals, the liver is usually regarded as a low-scattering tissue and is surrounded by adipose, kidneys, and heart, all of which have a high scattering property. This leads to a breakdown of the diffusion equation (DE)–based reconstruction method as well as a heavy computational burden for the simplified spherical harmonics equation (). Coupling the and DE provides a perfect balance between the imaging accuracy and computational burden. The coupled third-order and DE (CSDE)-based reconstruction method is developed for fluorescence tomographic imaging. This is achieved by doubly using the CSDE for the excitation and emission processes of the fluorescence propagation. At the same time, the finite-element method and hybrid multilevel regularization strategy are incorporated in inverse reconstruction. The CSDE-based reconstruction method is first demonstrated with a digital mouse-based liver cancer simulation, which reveals superior performance compared with the and DE-based methods. It is more accurate than the DE-based method and has lesser computational burden than the -based method. The feasibility of the proposed approach in applications of in vivo studies is also illustrated with a liver cancer mouse-based in situ experiment, revealing its potential application in whole-body imaging of small animals.