Mycophenolic acid (MPA), which is a potent immunosuppressant, has been widely used to prevent organ rejection after organ transplantation. In clinical practice, it is essential to monitor the free MPA concentration. Herein, convenient and fast electrochemical microsensing technology is developed for directly detecting the MPA concentration. To implement this method, ultrathin copper-based metal-organic framework (Cu-MOF) nanosheets with a thickness of about 6.6 nm are used to detect MPA. An analysis of electrochemical behavior reveals the direct electrochemical catalytic oxidation mechanism of MPA molecules on a Cu(II) tetrakis(4-carboxyphenyl)porphyrin (Cu-TCPP)-modified electrode. Furthermore, electrochemical testing results show that the ultrathin Cu-TCPP nanosheet-based microsensor exhibits high sensitivity and specificity for MPA in the nano- to micromolar range, with a detection limit of 10 nM. X-ray absorption spectroscopy (XAS) characterization reveals that the unsaturated metal ions in ultrathin nanosheets are the active sites responsible for boosting the catalytic oxidation of MPA molecules. High-performance liquid chromatography-tandem mass spectrometry further shows the catalytic oxidation product of MPA and that the phenolic hydroxyl group in the MPA molecule is the active site where the catalytic reaction occurs. The considerable sensing performance of the Cu-TCPP nanosheet-based microsensor proves that it is possible to develop a fast and convenient method for the direct high-frequency monitoring of immunosuppressive drugs.