In the recent years, interest in the synthesis of diclofenac derivatives has increased due to their exceptional biological activity. We present here the synthesis of some novel diclofenac derivatives through simple synthetic procedures, where the acylation of carbohydrazide compound 1 with chloroacetyl chloride in dioxane produced the compound 2. Chloroacetohydrazide compound 2 was further subjected to nucleophilic substitution reactions using different nucleophiles such as: hydrazine hydrate, thiosemicarbazide and p-aminobenzenesulfonamide to give the corresponding derivatives 3-5, respectively. Moreover, the reaction of the hydrazinyl compound 3 with active hydrogen species such as: ethyl acetoacetate and acetyl acetone in refluxed ethanol provided the corresponding pyrazolone derivatives 6 and 7, respectively. Furthermore, the reaction of previously reported diclofenac ester 8 with 1,2-diaminoethane gave the amino derivative 9. Finally, condensation reaction of the latter compound with benzaldehyde in dioxan furnished the corresponding Schiff's base compound 10, while its acylation with chloroacetyl chloride in dioxan produced 11. Different spectral (IR, NMR and Mass) and elemental analysis techniques were utilized to explore the structure of the synthesized compounds. All the synthesized compounds were tested for their in-vitro antibacterial activity against different strains of bacteria showing satisfactory results, and molecular docking study was performed to investigate the mode of action.