Blood glucose detection has been a critical issue in the medical field all over the world for a long time. Especially for diabetic patients, regular monitoring of blood glucose is necessary in their daily life. Nowadays, blood glucose detection mainly relies on fingertip blood glucose meters, which can provide the current blood glucose level in a short period of time. Meanwhile, there are several inconveniences and concerns, including the pain and discomfort of needle-prick blood collection, and the risk of infection at the needle-prick wound. Therefore, many researchers have devoted themselves to the development of non-invasive glucose detection in recent years. Till now, the practical glucose measurement in vivo is still faced with lots of difficulties. To get the signal or response of the molecules in vivo without penetration through the skin layers required two main properties. First of all, the biologic blockage and noise need to be avoided or overcame during the detection. Secondly, it’s necessary to enhance or amplify the signal due to relative low concentration of the target molecule under the skin. Here we introduce a surface-enhanced Raman spectroscopy (SERS) combined with external electric fields to achieve the goal of the detection in vivo without any invasive procedure. In the SERS system, we select 785 nm laser to reach deeper area through the skin layers while preventing the heat effect for tissue damaging. Next, with the signal differences from encountered with various concentration of glucose, 4-mercaptophenylboronic acid (4-MPBA) on silver nanoparticles (AgNPs) is able to quantify the glucose concentrations from the characteristic peak of the Raman shift. Furthermore, the combination with external electric fields induces coagulation of the sensing nanoparticles and provides many hotspots for SERS detection in vivo. We believed that this work is a great stepping stone of real time non-invasive glucose sensing in practical application.