The research details the synthesis, characterization, and antioxidant evaluation of five novel Schiff base derivatives of Isatin (A1–A5). Five derivatives (A1–A5) were synthesized via condensation reactions involving Isatin, p-phenylenediamine, and various aromatic aldehydes. Characterization was achieved through thin layer chromatography (TLC), melting point analysis, Fourier Transfer-Infrared Spectroscopy, 1H-Nuclear Magnetic Resonance (NMR) and 13C-Nuclear Magnetic Resonance (NMR). Using a 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, the antioxidant activity of these derivatives was assessed. The research emphasizes that the synthesized compounds exhibited statistically significant and biologically relevant antioxidant activities. These findings highlight the importance of specific substitution patterns on the Isatin scaffold in enhancing antioxidant efficacy. The work lays a foundation for further pharmacokinetic and structure-activity relationship studies and supports the potential of these Schiff base derivatives as promising candidates in the development of multifunctional therapeutic agents.