In the framework of tight-binding models and the Green’s function method, the mechanical modulation of the chirality-induced spin selectivity (CISS) in chiral molecular junctions is investigated. The results demonstrate that the CISS is weakened monotonically by stretching the molecule, while the change is nonmonotonic in the case of compression. A moderate compression enhances the CISS effect, while a strong compression induces destructive quantum interference (DQI) in the transmission, which generates large spin polarization around the DQI features associated with discrete and irregular spin polarization peaks. We explain the DQI mechanism in terms of interference of multiple paths in a simplified model for the chiral molecule. The variations of long-range electron hopping and spin-orbit coupling under molecular deformation are found to be crucial. For very strong compression, the DQI and the CISS are suppressed. This work proposes a feasible way to modulate the CISS in chiral molecular junctions by deepening our understanding of CISS in the presence of deformation.