Antimicrobial resistance poses a significant challenge to public health, and is worsened by the widespread misuse of antimicrobial agents such as triclosan (TCS) in personal care and household products. Leveraging the electrochemical reactivity of TCS’s phenolic hydroxyl group, this study investigates the electrochemical behavior of TCS on a Cu-based nano-metal–organic framework (Cu-BTC) surface. The synthesis of Cu-BTC via a room temperature solvent method, with triethylamine as a regulator, ensures uniform nanoparticle formation. The electrochemical properties of Cu-BTC and the signal enhancement mechanism are comprehensively examined. Utilizing the signal amplification effect of Cu-BTC, an electrochemical sensor for TCS detection is developed and optimized using response surface methodology. The resulting method offers a simple, rapid, and highly sensitive detection of TCS, with a linear range of 25–10,000 nM and a detection limit of 25 nM. This research highlights the potential of Cu-BTC as a promising material for electrochemical sensing applications, contributing to advancements in environmental monitoring and public health protection.