In the recent years, interest in the synthesis of diclofenac derivatives has increased due to their excep- tional 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 chlo- ride in dioxane produced the compound 2 . Chloroacetohydrazide compound 2 was further subjected to nucleophilic substitution reactions using different nucleophiles such as: hydrazine hydrate, thiosemicar- bazide and p -aminobenzenesulfonamide to give the corresponding derivatives 3-5 , respectively. More- over, 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 , re- spectively. 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 satisfac- tory results, and molecular docking study was performed to investigate the mode of action.