An N-arylmethyl activation strategy has been developed to solve the challenging problems associated with the direct C3–H thiolation reaction of quinolines, including trifluoromethyl thiolation, aryl thiolation, alkyl thiolation and phenyl selenylation. The relevant theoretical calculations of the local nucleophilic indices of quinolinium salts were performed to rationalize the site-selectivity. This metal-free protocol features a broad substrate scope, generally high yield, and good functional group compatibility. The practicality and potential application of this protocol were further demonstrated by a facile scale-up reaction and the late-stage thiolation of a wide range of quinoline-based biologically active complex molecules.