Late-life depression is characterized by both lower mood and poor cognitive performance, symptoms that often do not fully respond to current antidepressant medications. Nicotinic acetylcholine receptor (nAChR) agonists such as nicotine may serve as a novel therapeutic approach for this population. Both preclinical and preliminary clinical studies suggest that nAChR agonists can improve depressive behavior in animal models and improve mood in depressed individuals. Substantial literature also supports that nAChR agonists benefit cognitive performance, particularly in older populations. These potential benefits may be mediated by the effects of nAChR stimulation on neural network function and connectivity. Functional neuroimaging studies detail effects of nAChR agonists on the default mode network, central-executive network, and salience network that may oppose or reverse network changes seen in depression. We propose that, given the existent literature and the clinical presentation of late-life depression, nicotine or other nAChR agonists may have unique therapeutic benefits in this population and that clinical trials examining nicotine effects on mood, cognition, and network dynamics in late-life depression are justified.