Direct detection of drugs in the blood contributes to the study of pharmacokinetics, whereas the low-concentration blood drug makes this goal challenging. Here, silver nanoparticles (AgNPs) are used for direct detection in the blood environment. The finite element method is used to study the electric field enhancement of AgNPs in the blood environment. We study the Raman enhancement factors associated with AgNPs and study the effects of parameters such as the wavelength, medium environment, and nanoparticle distribution on near-field enhancement. The method for directly detecting oxaprozin (OXA) drug in the blood of mice is reported, which is based on surface-enhanced Raman scattering (SERS) detection. We prepare AgNPs with a diameter of 15 nm and further concentrated them as a SERS substrate to achieve low-concentration OXA solution detection in blood and aqueous environments. The minimum detection limit in the aqueous environment is 10 −6 M, and the detection limit in the blood is 10 −4 M (29.32 μg/mL), which is less than the peak blood drug concentration in clinical applications. Further analysis shows that OXA in the blood can be directly detected by SERS because of the characteristic peak of 1025 cm −1 , and the corresponding attribution is the C−C−C plane vibration. The numerical simulation of AgNPs and the detection of OXA solution in the blood environment indicate that SERS has a good application prospect in low-concentration blood drug detection.