Restraint stress (RS) is a condition affecting millions of people worldwide. The investigation of new therapies to alleviate the consequences of prolonged RS is much needed. Cotinine, a nicotine-derivative, has shown to prevent the decrease in cerebral synaptic density, working memory deficits, anxiety, and depressive-like behavior after prolonged restraint stress (RS) in mice. Furthermore, post-treatment with cotinine reduced the adverse effects of chronic RS on astrocyte survival and architecture. On the other hand, the nutritional supplement krill oil (KO), has shown to be beneficial in decreasing depressive-like behavior and oxidative stress. In this study, in the search for effective preventative treatments to be used in people subjected to reduced mobility, the effect of co-treatment with cotinine plus KO in mice subjected to prolonged RS was investigated. The results show that cotinine plus KO prevented the loss of astrocytes, the appearance of depressive-like behavior and cognitive impairment induced by RS. The use of the combination of cotinine plus KO was more effective than cotinine alone in preventing the depressive-like behavior in the restrained mice. The potential use of this combination to alleviate the psychological effects of reduced mobility is discussed.