Antimicrobial resistance (AMR) is recognized as a major global health threat, with treatment failures in microbial infections leading to numerous fatalities. One of the fundamental AMR mechanisms in bacteria involves the production of specific enzymes, such as beta-lactamase, which inactivate antibiotics before they reach the cell membrane. In response, our study develops an experimental approach using Surface-Enhanced Raman Scattering (SERS) to detect the presence of beta-lactamases and thereby confirm AMR. Recognized for its high sensitivity, multiplexing capabilities, robustness, and cost-effectiveness, SERS shows promising potential in biological applications. This research evaluates various SERS-active substrate designs, including a hybrid microfluidic channel with a nanohole sensing platform, a commercial paper-based SERS substrate with gold nanoparticles, and an electric field-enhanced SERS system, for detecting meropenem, an antibiotic from the group of beta-lactams, at a concentration of 10 mg/L. Additionally, we established a cell-test protocol for rapid detection of β-lactamase-producing bacteria. Preliminary results show that a SERS-based assay comprising meropenem “sandwiched” between a silver nanostructured SERS substrate and electrokinetically captured gold nanostars from a colloidal suspension can provide high detection sensitivity. The latter assay also provides more stable background signals compared to established commercial paper-based SERS chips. The observed Raman spectra for meropenem and its degradation products indicate that beta-lactam ring cleavage leads to an increase in peak intensity at 1328 and 1170 cm-1 and decreases at 836 and 920 cm-1. To enable the use of this method in clinical applications, future work should incorporate on-chip microfluidic testing to automate the workflow and identify, as well as quantify SERS, signal changes in other antibiotics and beta-lactamases.