Semiconductor-based surface enhanced Raman scattering (SERS) substrate design has attracted much interest due to the excellent photoelectronic and biochemical properties. The structural change caused by twin in semiconductor will have an influence on improving the Raman signals enhancement based on the chemical mechanism (CM). Here, we demonstrated the twin in semiconductor ZnSe nanowires as an ultrasensitive CM-based SERS platform. The SERS signals of the rhodamine 6G (R6G) and crystal violet (CV) molecules adsorbed on twin-ZnSe nanowires could be easily detected even with an ultralow concentration of 10-11 M and 10-8 M, respectively, and the corresponding enhancement factor (EF) were up to 6.12 × 107 and 3.02 × 105, respectively. In addition, the charge transfer (CT) between the twin-ZnSe nanowires and R6G molecule has been demonstrated theoretically with first-principles calculations based on density-functional theory (DFT). These results demonstrated the proposed ZnSe nanowires with twin as SERS substrate has a broader application in the field of biochemical sensing.