© 2022 Elsevier B.V.Even though amoxicillin is used as an antibacterial drug in some foods such as fish, chick, etc. However, the use of amoxicillin in the food industry is prohibited. Therefore, rapid detection and sensitive detection at ultra-low concentration of amoxicillin is very important for human. Surface enhanced Raman scattering (SERS) is fast and reliable method to determine the molecules at ultra-low concentration. In this study, silver nanocubes were synthesized and used as SERS active substrate. The synthesized Ag NCs exhibit an excellent sensitivity towards the detection of amoxicillin at the lowest concentration of 10−9 M based on the effect resulting from Ag NCs leading to the high electromagnetic effect and chemical mechanism. The dynamic linear regression between the Raman intensity and amoxicillin concentration over seven orders of magnitude (from 10−4 to 10−9 M) was excellent with high reliability (R2 = 0.99). On the one hand, SERS substrate can be used after storing for 20 days. Because Ag NCs also demonstrated remarkable recyclability, reproducibility, and chemical stability. As a result, Ag NCs can be used as a potential SERS substrate to detect amoxicillin at ultra-low concentration.