Small molecule compounds are necessary to detect with high sensitivity since they may cause a strong effect on the human body even in small concentrations. But existing methods used to evaluate small molecules in blood are inconvenient, costly, time-consuming, and do not allow for portable usage. In response to these shortcomings, we introduce a complementary metal-oxide-semiconductor bio-microelectromechanical system (CMOS BioMEMS) based piezoresistive membrane-bridge (MB) sensor for detecting small molecule (phenytoin) concentrations as the demonstration. Phenytoin is one of anticonvulsant drugs licensed for the management of seizures, which has a narrow therapeutic window hence a level of concentration monitoring was needed. The MB sensor was designed to enhance the structural stability and increase the sensitivity, which its signal response increased 2-fold higher than that of the microcantilever-based sensor. The MB sensor was used to detect phenytoin in different concentrations from 5 to 100 μg/mL. The limit of detection of the sensor was 4.06 ± 0.15 μg/mL and the linear detection range was 5-100 μg/mL, which was within the therapeutic range of phenytoin concentration (10-20 μg/mL). Furthermore, the MB sensor was integrated with an on-chip thermal effect eliminating modus and a reaction tank on a compact chip carrier for disposable utilization. The required amount of sample solution was only 10 μL and the response time of the sensor was about 25 minutes. The nano-mechanical MB sensing method with thermal effect compensation is specific, sensitive, robust, affordable and well reproducible; it is, therefore, an appropriate candidate for detecting small molecules.