Acetylcholinesterase has been a promising target for the development of potential treatments for cognitive deterioration. The deleterious effect of oxidative stress on the learning and memory paradigms of an individual has also been well documented. In view of this, the present study demonstrates the design, synthesis, and pharmacological evaluation of 2, 5 disubstituted 1,3,4 thiadiazole derivatives. Twenty-two molecules (28-50) were designed and the molecular docking study performed to envisage the binding mode of the designed compounds also suggested that these compounds bind appreciably to the amino acids present in the active site of the recombinant human acetylcholinesterase (rhAChE). Based upon docking analysis, Five novel hybrids (28, 29, 30, 32, and 36) have been synthesized by employing suitable synthetic procedures and characterized by various spectral and elemental techniques. Further, these synthesized compounds were studied in the pharmacokinetic study and evaluated against behavioral alterations using step-down passive avoidance and escape learning protocol at a dose of 0.5 mg/kg with reference to the standard, donepezil. All the synthesized compounds were evaluated for their in vitro acetylcholinesterase (AChE) inhibition at five different concentrations using mice brain homogenate as the source of the enzyme. Biochemical estimation of markers of oxidative stress has also been carried out to assess the role of synthesized molecules on oxidative damage induced by ascorbic acid. Compounds 28 and 36 established a significant acetylcholinesterase inhibition activity. These compounds also decreased ascorbic acid-induced oxidative stress, thus serving as promising leads for the amelioration of oxidative stress-induced cognitive decline. The results indicated that these compounds could be investigated further as AChE and oxidative stress inhibitors for the treatment of cognitive dysfunction