A series of previously synthesized conjugates of tacrine and salicylamide was extended by varying the structure of the salicylamide fragment and using salicylic aldehyde to synthesize salicylimine derivatives. The hybrids exhibited broad-spectrum biological activity. All new conjugates were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. The structure of the salicylamide moiety exerted little effect on anticholinesterase activity, but AChE inhibition increased with spacer elongation. The most active conjugates were salicylimine derivatives: IC values of the lead compound were 0.0826 µM (AChE) and 0.0156 µM (BChE), with weak inhibition of the off-target carboxylesterase. The hybrids were mixed-type reversible inhibitors of both cholinesterases and displayed dual binding to the catalytic and peripheral anionic sites of AChE in molecular docking, which, along with experimental results on propidium iodide displacement, suggested their potential to block AChE-induced -amyloid aggregation. All conjugates inhibited Aβ self-aggregation in the thioflavin test, and inhibition increased with spacer elongation. Salicylimine and salicylamide with (CH) spacers were the lead compounds for inhibiting Aβ self-aggregation, which was corroborated by molecular docking to Aβ. ABTS-scavenging activity was highest for salicylamides , intermediate for salicylimines , low for F-containing salicylamides , and non-existent for methoxybenzoylamides and difluoromethoxybenzoylamides . In the FRAP antioxidant (AO) assay, the test compounds displayed little or no activity. Quantum chemical analysis and molecular dynamics (MD) simulations with QM/MM potentials explained the AO structure-activity relationships. All conjugates were effective chelators of Cu, Fe, and Zn, with molar compound/metal (Cu) ratios of 2:1 () and ~1:1 (). Conjugates exerted comparable or lower cytotoxicity than tacrine on mouse hepatocytes and had favorable predicted intestinal absorption and blood-brain barrier permeability. The overall results indicate that the synthesized conjugates are promising new multifunctional agents for the potential treatment of AD.