Nucleic acid is the most basic genetic material in life. It is of great significance to carry out a nucleic acid molecular diagnosis to promote the development of human health and medical treatment. Surface-enhanced Raman spectroscopy (SERS), as a rapid, nondestructive testing technique, has the advantages of simple sample preparation, low interference of water, non-invasion, and real-time detection. It has shown great application potential in the fields of nucleic acid detection, pathogenic microorganism detection and tumor accurate molecular diagnosis. Based on the application of clinical examination, a brief tutorial on SERS technical principle and SERS enhancement theory are given first of all. Then the review mainly summarizes the recent trends and developments of SERS in the detection of nucleic acid. The traditional label-free SERS detection is to detect the Raman signal of nucleic acid itself directly, but its sensitivity and specificity can not meet the detection requirements. In the labeled SERS detection, the Raman reporter molecule is connected with the target nucleic acid by DNA probe. The qualitative and quantitative detection of target DNA/RNA is realized by detection and analysis of the Raman reporter molecular signal, which demonstrates the advantage of SERS as “fingerprint” and achieves the purpose of high throughput detection with good control lability and stability. According to different Raman signal amplification methods, the labeled SERS analysis on nucleic acid detection mainly include “sandwich structure”, signal turn “on /off”, and hybridization chain reaction (HCR) signal amplification method, especially the “sandwich structure” detection strategy has the highest sensitivity. These researches have demonstrated that the application of SERS in DNA/RNA detection could over come the shortcoming of traditional methods, and provide a rapid, effective and sensitive analytical tool for real-time monitoring of nucleic acid and accurate real-time diagnosis of clinical diseases. At the same time, there are still great challenges for the application of SERS technology in clinical application: (1) The poor binding stability of Raman reporter molecules to nanoparticles makes it difficult to realize the high sensitivity SERS probe which can be stored stably for a long time. (2) the composition of clinical, biological samples is complex, and there are many interference factors to SERS detection signal, so it is necessary to select effective data analysis methods. (3) The research of highly sensitive, easy to operate, low-cost Raman spectrometer is the key to transform SERS technology into practical application. In the future, with the deepening of SERS and the cross-development of multi-disciplinary, SER technology is expected to be widely used in nucleic acid detection and the whole biomedical detection field, and provide a powerful analytical technology for life science.