The surface-enhanced Raman scattering (SERS) technique has demonstrated great advantages, such as high sensitivity and minimal equipment requirement. However, its application is largely hindered by high-expense SERS substrates. Here, we develop a low-cost and easily accessible SERS platform based on natural cuttlebone-derived organic matrix (CDOM) for rapid and portable detection of the Bacillus cereus spore biomarker, 2,6-pyridinedicarboxylic acid (DPA). The natural porous structure of CDOM helps achieve a significant load of Ag nanoparticles (AgNPs). By adjusting the amount of NaOH in Tollens' reagent, more uniform AgNPs can be obtained on the surface of CDOM. The pyridine N atom or carboxylic acid O atom of DPA acts on the AgNP surface to produce the characteristic peak of SERS. Meanwhile, internal standard materials are added to resist the instability caused by natural materials. The SERS substrate realized the quantitative detection of DPA within 30 min. The linear range is from 40 to 1000 nM, and the detection limit is 8.62 nM. The sensor can detect bacterial spores in foods, such as milk. This method can be used as a reliable idea and an example for the practical application of biologically derived materials.