Surface property that strongly affects physical and chemical performances of inorganic nanocrystals (NCs) is a key enabler for NCs applications. Here, we report a facile, versatile and general strategy for reactive removal of NCs surface ligands based on electrophilic substitution reaction, in which an electrophile directly reacts with the electron-rich coordinating headgroup of surface-tethered ligands to form a non-coordinating product. This process leads to the break of NC-ligand bond, thereby achieving reactive removal of surface ligands. Based on this strategy, various hydrophobic NCs with different compositions and morphologies can be transferred into polar and hydrophilic media while preserving their size and shape. More importantly, the treated NCs present a great improvement in catalytic and biological performances in comparison with the untreated counterparts. This work not only provides a versatile ligand removal strategy for NCs surface modification but also opens up more opportunities for applications in the fields of electronics, catalysis and biotechnology.