A series of pyrazolo[1,5-c]quinazolines as EGFR inhibitors was designed and synthesized by highly efficient and novel multicomponent route involving Pd-catalyzed tandem one-pot four-component reaction. The reaction proceeds with good functional group tolerance under a simple condition with excellent regioselectivity and high efficiency. Target compounds were screened against cancer cell lines MDA-MB-231, A549 and H1299. Of these, 9b and 10b exhibited superior anticancer activity (IC < 2.5 μM) to erlotinib and gefitinib. Synthetics were able to inhibit EGFR mediated kinase activity, induced ROS in cancer cells promoting mitochondrial mediated apoptosis via halting cell cycle progression at G1 phase.