Rapid and in-depth exploration of the chemical space of high molecular weight synthetic polypeptides via the ring-opening polymerization (ROP) of N-carboxyanhydride (NCA) is a viable approach towards protein mimics and functional biomaterials. Here, we develop an efficient chemistry for the high throughput diversification of polypeptides based on a click-like reaction between selenolate and various electrophiles in aqueous solutions. With the assistance of automation and machine learning, iterative exploration of the random heteropolypeptides (RHPs) library efficiently and effectively identifies hit materials from a model system of which we have little prior knowledge. This automated and high-throughput platform provides a useful interface between wet and dry experiment, which would accelerate the discovery of new polypeptide materials for unmet challenges such as de novo design of artificial enzyme, biomacromolecule delivery, and understanding of intrinsically disordered proteins.