AbstractAlzheimer’s disease (AD) is a chronic, progressive brain degenerative disease that is common in the elderly. So far, there is no effective treatment. The multi-target-directed ligands (MTDLs) strategy has been recognised as the most promising approach due to the complexity of the pathogenesis of AD. Herein, novel salicylic acid–donepezil–rivastigmine hybrids were designed and synthesised. The bioactivity results exhibited that5awas a reversible and selectiveeqBChE inhibitor (IC50= 0.53 μM), and the docking provided the possible mechanism. Compound5aalso displayed potential anti-inflammatory effects and significant neuroprotective effect. Moreover,5aexhibited favourable stabilities in artificial gastrointestinal solution and plasma. Finally,5ademonstrated potential cognitive improvement in scopolamine-induced cognitive dysfunction. Hence,5awas a potential multifunctional lead compound against AD.