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Recent advancements in high-throughput screening have focused on using multi-parametric readouts to characterize drug compound effects. While high-content imaging is commonly used, it only captures endpoint images of fixed cells. Here, we report a semiconductor 96-microplate platform which performs real-time, label-free impedance “imaging” of live-cells. An array of 64×64=4,096 electrodes/well provides spatial resolution of 25 µm and enables multi-frequency, field-based measurements to capture >20 morphological and functional parameters. This represents a major advancement over current electronic microplates which use 2 electrodes/well for single parameter measurement. Unique characteristics including tissue barrier, cell-surface attachment, transepithelial water transport, cell size and motility are captured every 5-15 min during the experiment time-course. Eleven cell types ranging from primary epithelial to suspension are functionally characterized and proof-of-concept screens using 341 FDA approved compounds highlight the ability to perform mechanism of action (MOA) profiling. Compounds increasing tissue barrier with a previously unreported MOA were identified, an illustrative example of phenotypic discovery in the context of gut barrier diseases. The combination of MOA profiling and direct translatability of functional phenotypes promises to unlock new avenues in phenotypic high-throughput screening.