Semiconductor-based surface-enhanced Raman spectroscopy (SERS) substrates represent a new frontier in the field of SERS. However, the application of semiconductor materials as SERS substrates is still seriously impeded by their low SERS enhancement and inferior detection sensitivity, especially for non-metal-oxide semiconductor materials. Herein, we demonstrate a general oxygen incorporation-assisted strategy to magnify the semiconductor substrate–analyte molecule interaction, leading to significant increase in SERS enhancement for non-metal-oxide semiconductor materials. Oxygen incorporation in MoS2 even with trace concentrations can not only increase enhancement factors by up to 100,000-fold compared with oxygen-unincorporated samples but also endow MoS2 with low limit of detection below 10−7 M. Intriguingly, combined with the findings in previous studies, our present results indicate that both oxygen incorporation and extraction processes can result in SERS enhancement, probably due to the enhanced charge-transfer resonance as well as exciton resonance arising from the judicious control of oxygen admission in semiconductor substrate.