High-throughput screening of C. elegans for drug discovery and gene function would require technological advancements for high-resolution imaging operating at high speeds. To enable both high-speed and high-resolution imaging of multiple C. elegans populations, we developed an automated and large-scale microfluidic imaging platform. The platform includes a large-scale microfluidic chip with 96 wells designed in standard microtiter plate format and densely packed trapping channels for each well. The channels are uniquely designed to immobilize approximately 4,000 animals simultaneously in 3 minutes. The automated imaging platform takes 15 z-stack images of all trapped animals, capturing their whole volume in less than 16 minutes with a resolution of a micron. An automated graphical user interface (GUI) loads all the images, identifies single animal and perform image processing steps for phenotyping. Using this platform, we screened more than 100,000 animals of a polyglutamine aggregation (PolyQ) model using a total number of 25 chips. We tested the efficacy of ~1,000 FDA approved drugs in improving the aggregation phenotype in the PolyQ model to identify possible proteostasis modulators with a Z’-factor of 0.80. The study resulted in four potential hits using the protein aggregation model. The platform provides a leap forward for high-throughput screening of other C. elegans disease models with cellular or sub-cellular phenotypes.