The reproducible degradation of thin polymer films in the presence of an analyte or a reaction product of an analyte has potential applications in the development of highly sensitive, disposable biosensors. In this study, a novel combination of quartz crystal microbalance (QCM) and electrochemical impedance spectroscopy (EIS) has been developed to monitor the degradation of thin polymer films. Unlike a conventional QCM, the instrument described here allows rapid in situ measurement of quartz crystal impedance spectra. Simultaneously, classical electrochemical impedance spectra are measured in situ, affording the polymer film capacitance and bulk resistance. The combination of QCM impedance and classical EIS provides a wealth of information about the process of degradation of thin polymer films such as mass variation, swelling, delamination, viscoelasticity, and pore formation. Three different systems have been analyzed with this experimental setup; in two of the systems, polymer degradation was promoted by hydrolytic enzymes, and in the third one by a pH change. The results obtained show that the degradation of these three systems follows very different mechanisms. It is also underlined how the complementary information obtained by the two techniques allows a detailed description of the dissolution process.