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The diverse nature of Alzheimer's disease (AD) has prompted researchers to develop multi-functional agents. Herein, we have designed and synthesized molecular hybrids of 2-pyridylpiperazine and 5-phenyl-1,3,4-oxadiazoles. Biological activities of synthesized compounds suggested significant and balanced inhibitory potential against target enzymes. In particular, compound 49 containing 2,4-difluoro substitution at terminal phenyl ring considered as most potential lead with inhibition of acetylcholinesterase (hAChE, IC 50 = 0.054 μM), butyrylcholinesterase (hBChE, IC 50 = 0.787 μM) and beta-secretase-1 (hBACE-1, IC 50 = 0.098 μM). The enzyme kinetics study of 49 against hAChE suggested a mixed type of inhibition (Ki = 0.030 μM). Also, 48 and 49 showed significant displacement of propidium iodide from the peripheral anionic site (PAS) of hAChE, excellent blood-brain barrier (BBB) permeability in parallel artificial membrane permeation assay (PAMPA), and neuroprotective ability against SH-SY5Y neuroblastoma cell lines. Further, 49 also exhibited anti-Aβ aggregation activity in self- and AChE-induced thioflavin T assay, which was ascertained by morphological characterization by atomic force microscopy (AFM). Moreover, in vivo behavioral studies signified learning and memory improvement by compound 49 in scopolamine- and Aβ-induced cognitive dysfunctions performed on Y-maze and Morris water maze. The ex vivo studies suggested decreased AChE activity and antioxidant potential of compound 49 , with good oral absorption characteristics ascertained by pharmacokinetic studies. Image 1 • Design and synthesis of 2-pyridylpiperazine and 5-phenyl-1,3,4-oxadiazoles hybrids. • Compounds 48 and 49 exhibited balanced inhibition of AChE and BACE-1. • Propidium iodide displacement and inhibition of Aβ aggregation by 48 and 49. • Ex vivo study of rat hippocampal homogenates suggested antioxidant potential. • Amelioration of scopolamine- and Aβ-induced cognitive impairment in AD rat models. [ABSTRACT FROM AUTHOR]