A rational approach to investigate the effect of molecular orientation on the intensity of chemical enhancement using graphene-enhanced Raman spectroscopy (GERS) is developed. A planar molecule, copper phthalocyanine (CuPc), is used as probe molecule. Annealing allows the CuPc molecule in a Langmuir–Blodgett film to change orientation from upstanding to lying down. The UV–visible absorption spectra prove the change of the molecular orientation, as well as the variation of the interaction between the CuPc molecule and graphene. The Raman spectra of the molecule in the two different orientations are compared and analyzed. The results show that chemical enhancement is highly sensitive to the molecular orientation. The different molecular orientations induce different magnitudes of the interaction between the molecule and graphene. The stronger the interaction, the more the Raman signal is enhanced. Furthermore, the sensitivity of GERS to molecular orientation is promising to determine the orientation of the molecule on graphene. Based on this molecular orientation sensitive Raman enhancement, quantitative calculation of the magnitude of the chemical enhancement is implemented for a series of Pc derivatives. It shows that the magnitude of the chemical enhancement can be used to evaluate the degree of interaction between the molecules and graphene. Moreover, an understanding of the chemical enhancement in GERS is promoted and the effect of molecular orientation on the intensity of chemical enhancement is explained.