A series of novel tacrine-isatin Schiff base hybrid derivatives (7a-p) were designed, synthesized and evaluated as multi-target candidates against Alzheimer's disease (AD). The biological assays indicated that most of these compounds displayed potent inhibitory activity toward acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) and specific selectivity for AChE over BuChE. It was also found that they act as excellent metal chelators. The compounds 7k and 7m were found to be good inhibitors of AChE-induced amyloid-beta (Aβ) aggregation. Most of the compounds inhibited AChE with the IC50 values, ranging from 0.42 nM to 79.66 nM. Amongst them, 7k, 7m and 7p, all with a 6 carbon linker between tacrine and isatin Schiff base exhibited the strongest inhibitory activity against AChE with IC50 values of 0.42 nM, 0.62 nM and 0.95 nM, respectively. They were 92-, 62- and 41-fold more active than tacrine (IC50 = 38.72 nM) toward AChE. Most of the compounds also showed a potent BuChE inhibition among which 7d with an IC50 value of 0.11 nM for BuChE is the most potent one (56-fold more potent than that of tacrine (IC50 = 6.21 nM)). In addition, most compounds exhibited the highest metal chelating property. Kinetic and molecular modeling studies revealed that 7k is a mixed-type inhibitor, capable of binding to catalytic and peripheral site of AChE. Our findings make this hybrid scaffold an excellent candidate to modify current drugs in treating Alzheimer's disease (AD).