Nuclear morphological changes are highly correlated with developmental progression, cellular differentiation, and aging. Aberrant nuclear morphology is associated with a multitude of disease states including cancers and can be used as a phenotype to screen for the activity of novel drug candidates. Conventional methods to detect and measure nuclear morphological changes require nuclear staining with dye and subsequent image acquisition and analysis by microscopy. We assessed the ability to perform nuclear morphological profiling using VisionSort and show that it can be used to provide a sensitive fluorescence and label-free assessment of nuclear morphology with potential applications in a variety of biopharmaceutical workflows.