Cancer is the ruling cause of mortality worldwide. Chemotherapeutic toxicity and drug resistance have provided impulsion for the formulation of new anticancer agents. Receptor tyrosine kinases (RTKs) are the most activated cell surface receptors for copious polypeptide growth factors, cytokines, and hormones that play a considerable role in cancer initiation, promotion, and progression. Natural products are a prime source of new anticancer drugs and their leads. The objective of computer-aided drug design (CADD) is to enhance the set of compounds with prudent active drug-like properties and eliminate inactive, toxic, poor absorption, distribution, metabolism, and excretion toxicity (ADME/T) compounds. In the present chapter, in silico advancement of anticancer natural compounds and molecular mechanisms of action of flavonoids, viz., genistein, myricetin, quercetin, luteolin, morin, kaempferol, catechin, and epigallocatechin gallate (EGCG), on RTK and PI3K signaling pathway attributing to their potential anticancer activity have been discussed.