Carbon quantum dots (CDs) with favorable luminescent features for biphotonic applications have attracted much interest in modulating their photoluminescence (PL) efficiency. A surface state with various defects is believed to play a key role in the emissive intensity. Here, pressure-induced quenching of PL is observed in red emissive CDs (R-CDs) and is ascribed to defects in carbon cores upon compression. In the power-law fitting to the excitation power-dependent PL of R-CDs at high pressure, the coefficient k parameter related to the emissive mechanism decreases from 1 under ambient pressure to much less than 1 under the application of pressure, suggesting a transition from single exciton recombination to defect-related emission. With the k parameter decreasing to 0.69 at 1.6 GPa, the pressure-induced defects reduce the PL intensity by approximately one order of magnitude. Furthermore, the attenuation and broadening of the G band characterizing the sp2 hybrid structure of carbon cores in the Raman spectra for R-CDs at high pressure support that the pressure-induced lattice relaxation impairs the crystalline symmetry of the carbon core and results in the dramatic quenching of PL. Our results highlight the importance of the well-crystallized carbon core in designing CDs with high quantum yields.