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The present study deals with developing novel 1,3,5‐triazine‐nicotinohydrazide derivatives as potent CDK9 inhibitors in a straightforward synthetic route with potent anti‐osteosarcoma activity. The most potent CDK9 inhibitor compound 5k inhibits proliferation of MG‐63 cells via induction of apoptosis and G2/M cell cycle arrest. It reduces tumor progression in the patient‐derived orthotopic xenograft (PDOX) mouse model with significant antioxidant and anti‐inflammatory activity. In tumor tissue homogenates, it caused significant inhibition of CDK9 and inhibited the phosphorylation of RNAPII ser2 and reduced MCL‐1 expression in Western blot analysis. Compound 5k also showed considerable bioavailability in SD mice. Our results demonstrated that compound 5k inhibits growth of OS in vitro and in vivo via inhibition of CDK9 which attenuated the downstream phosphorylation of RNAPII ser2 and represses expression of the anti‐apoptotic protein, MCL‐1 for the induction of apoptosis in OS. [ABSTRACT FROM AUTHOR]