This paper presents a novel method for monitoring drug cytotoxicity using a hybrid microfluidic CMOS platform. This platform consists of an array of 8 × 8 capacitive sensors integrated with a readout circuit on the same chip. In this paper, we present a layer-by-layer (LBL) polyelectrolyte deposition technique to coat the surface of microelectrodes realized in the top most metal layer in 0.35-μm CMOS process. This process successfully enhances the biocompatibility of sensing microelectrodes and consequently increases the cell viability over a three-day period. Herein, we demonstrate and discuss the advantage of the proposed platform for drug cytotoxicity as well as cellular growth monitoring. This CMOS sensing platform possesses a wide output dynamic range and allows tracking cell growth at initial cell concentrations ranging from 10 to 200 k Cells/ml. We also use a standard Alamarblue cell-based assay and Geneticin selective antibiotic (G418) as control and cytotoxic drugs introduced to non-resistant H1299 and resistant Hek293 cell lines, respectively. Furthermore, a low complexity microfluidic packaging technique is presented to create and bond micro-wells on CMOS chip for rapid test and characterization. With the potential to perform label-free cellular analysis, the proposed platform opens an avenue to transition from traditional to smart cellular analysis techniques suitable for a variety of biological applications, in particular high throughput cell-based drug testing.