This study reports a reconfigurable microfluidic platform comprising multifunctional building blocks and interfaces for high-throughput screening of nonhormonal contraceptives. The platform has three layers of microfluidic building blocks. The top layer consists of interchangeable microchannel building blocks in 3D for liquid handling (e.g., compound libraries, chemical concentration gradients, and drug cocktail mixers). The middle layer incorporates a multiwell array with embedded membrane filters for oocyte culture, medium exchange, enzymatic cumulus cell removal, washing, and fluorescence staining. The bottom layer can be reconfigured for waste collection, oocyte culture, and high-resolution microscopy. The reconfigurability of the platform is enabled by reversible and robust elastomer-based interconnects between building blocks. We demonstrate the platform for performing contraceptive drug loading, in situ oocyte incubation, enzymatic cumulus cell digestion, fluorescence staining, and on-chip imaging in a cumulusoocyte complex (COC) expansion assay for screening nonhormonal contraceptives.