Cancer is a complex illness that kills millions of people globally each year. Its origin and growth are highly complicated. The treatment of cancer includes surgery, chemotherapy, and radiation, which can be used separately or in conjunction. However, side effects and multidrug resistance (MDR) are serious obstacles to effective cancer treatment. Chalcone family members have received high interest because of their synthetic and biosynthetic production, besides the broad range of their biological activities. Chalcone targets a wide range of molecular cascades that share in the control of apoptosis and cell cycle growth. Chalcone hybrids especially with xanthine derivatives have approved antineoplastic activity. This review highlights the mechanisms of action of chalcone alone or in hybrids in cancer cells with impact on lung cancer especially non-small cell lung cancer. It also clears the expected mechanisms that regulate apoptosis and cell cycle arrest as an important target in cancer.