Alzheimer's disease (AD) is a neurodegenerative disease mainly characterized by progressive cognitive dysfunction and memory impairment. Recent studies have shown that regulating silent information regulator 1 (SIRT1) expression has a significant neuroprotective effect, and SIRT1 may become a new therapeutic target for AD. Natural molecules are an important source of drug development for use in AD therapy and may regulate a wide range of biological events by regulating SIRT1 as well as other SIRT1-mediated signaling pathways. This review aims to summarize the correlation between SIRT1 and AD and to identify in vivo and in vitro studies investigating the anti-AD properties of natural molecules as modulators of SIRT1 and SIRT1-mediated signaling pathways. A literature search was conducted for studies published between January 2000 and October 2022 using various literature databases, including Web of Science, PubMed, Google Scholar, Science Direct, and EMBASE. Natural molecules, such as resveratrol, quercetin, icariin, bisdemethoxycurcumin, dihydromyricetin, salidroside, patchouli, sesamin, rhein, ligustilide, tetramethoxyflavanone, 1-theanine, schisandrin, curcumin, betaine, pterostilbene, ampelopsin, schisanhenol, and eriodictyol, have the potential to modulate SIRT1 and SIRT1 signaling pathways, thereby combating AD. The natural molecules modulating SIRT1 discussed in this review provide a potentially novel multi-mechanistic therapeutic strategy for AD. However, future clinical trials need to be conducted to further investigate their beneficial properties and to determine the safety and efficacy of SIRT1 natural activators against AD.