This study presents an efficient strategy for constructing 1,2-difunctionalized quinoline derivatives via the multicomponent cascade coupling of N-heteroaromatics with alkyl halides and different terminal alkynes. This reaction was achieved through sequential functionalization at the one- and two-positions of quinolines, which displayed a broad substrate scope, environmental friendliness, excellent functional group tolerance, high atom efficiency, and chemoselectivity. The multicomponent coupling involved the abnormal construction of new C-N, C═C, and C═O bonds in one pot. The applicability of this method was further demonstrated by the late-stage functionalization of complex drug molecules under the established conditions.