High-resolution light-microscopy and high-throughput screening are two essential methodologies for characterizing cellular phenotypes. Optimally combining these methodologies in cell-based screening to test detailed molecular and cellular responses to multiple perturbations constitutes a major challenge. Here we describe the development and application of a screening microscope platform that automatically acquires and interprets sub-micron resolution images at fast rates. The analysis pipeline is based on the quantification of multiple subcellular features and statistical comparisons of their distributions in treated vs. control cells. Using this platform, we screened 2200 natural extracts for their effects on the fine structure and organization of focal adhesions. This screen identified 15 effective extracts whose fractionation and characterization were further analyzed using the same microscope system. The significance of combining resolution, throughput and multi-parametric analyses for biomedical research and drug discovery is discussed.