A novel series of 2,4-dichlorophenoxymethyl-based derivatives 4-18 bearing various nitrogenous heterocyclic systems have been designed and synthesized through molecular hybridization approach. The anti-proliferative activity of all newly synthesized derivatives was established against human HCT-116 and MCF-7 cancer cell lines. The structure–activity relationship (SAR) studies exhibited that the derivatives incorporated with pyrido[3,2-d]pyrimidine, naphtho[2,3-e][1,3]oxazine-5-sulfonic acid, benzo[d]thiazole and benzo[d]oxazole scaffolds revealed the highest cytotoxic activities comparing with doxorubicin as a reference drug. The promising derivatives 5, 9, 13 and 15 were subjected to enzymatic inhibitory assessment against CDK-2/cyclin A2 using roscovitine as a standard. Concerning their effects upon the apoptotic process, they upregulated Bax, p-53 and caspase-3 levels and downregulated Bcl-2, causing induction of apoptosis. Moreover, the in silico molecular docking was applied to investigate the possible binding modes and orientations within the active site of CDK-2.