A new series of pyridine-2-one and pyrazole derivatives were designed and synthesized based on cyanoacrylamide derivatives containing 2,4-dichlro aniline and 6-methyl 2-amino pyridine as an aryl group. Condensation of cyanoacrylamide derivatives 3a–d with different active methylene (malononitrile, ethyl cyanoacetate cyanoacetamide, and ethyl acetoacetate) in the presence of piperidine as basic catalyst afforded the corresponding pyridinone derivatives 4a–c, 5, 9, and 13. Furthermore, the reaction of cyanoacrylamide derivatives 3a–d with bi-nucleophile as hydrazine hydrate and thiosemicarbazide afforded the corresponding pyrazole derivatives 14a,b and 16. The newly designed derivatives were confirmed and established based on the elemental analysis and spectra data (IR, 1H NMR, 13C NMR, and mass). The in vitro antibacterial activity was evaluated against four bacterial strains with weak to good antibacterial activity. Moreover, the results indicated that the most active derivatives 3a, 4a, 4b, 9, and 16 might lead to antibacterial agents, especially against B. subtilis and P. vulgaris. The DFT calculations were performed to estimate its geometric structure and electronic properties. In addition, the most active pyridinone and pyrazole derivatives were further evaluated for in silico physicochemical, drug-likeness, and toxicity prediction. These derivatives obeyed all Lipinski’s and Veber’s rules without any violation and displayed non-immunotoxin, non-mutagenic, and non-cytotoxic. Molecular docking simulation was performed inside the active site of Topoisomerase IV (PDB:3FV5). It displayed binding energy ranging from -14.97 kcal/mol to -18.86 kcal/mol with hydrogen bonding and arene–cation interaction. Therefore, these derivatives were suggested to be good antibacterial agents via topoisomerase IV inhibitor. Graphical abstract