Metal-organic frameworks (MOFs) have attracted widespread interest due to their unique and unprecedented advantages in microstructures and properties. Besides, surface-enhanced Raman scattering (SERS) technology has also rapidly developed into a powerful fingerprint spectroscopic technique that can provide rapid, non-invasive, non-destructive, and ultra-sensitive detection, even down to single molecular level. Consequently, a considerable amount of researchers combined MOFs with the SERS technique to further improve the sensing performance and broaden the applications of SERS substrates. Herein, representative synthesis strategies of MOFs to fabricate SERS-active substrates are summarized and their applications in ultra-sensitive biomedical trace detection are also reviewed. Besides, relative barriers, advantages, disadvantages, future trends, and prospects are particularly discussed to give guidance to relevant researchers.