An increasing body of evidence suggests an implication of altered thiamine metabolism in mental illnesses, including depression and Alzheimer’s disease. Here, we examined the effects of a two-week treatment with thiamine (200 mg/kg/day) or benfotiamine (200 mg/kg/day, a synthetic thiamine precursor of high bioavailability, on learning of C57 mice in step down avoidance (SDA) and fear conditioning (FC) tests and depressive-like behavior in the modified forced swimming test (modFST). In addition, we investigated the effects of these drugs on brain gene expression of Glycogene Synthase Kinase 3beta (GSK3b), a regulatory factor that is involved in both above-mentioned mental conditions. Benfotiamine, but not thiamine significantly increased contextual learning in C57 mice in the step-down paradigm and acquisition of fear conditioning during weak training. Both compounds have improved the extinction of contextual fear conditioning memory and did not alter the acquisition of fear conditioning during strong training. Also, we found that both treatments reduced depressive-like behavior in mice, as shown by diminished duration of floating behavior in the modified forced swim test. With the modified forced swimming test applied here, an additional swimming session was carried out 120 hours after the first trial and resulted in increased mRNA levels of GSK3b in the prefrontal cortex, which correlated with duration of floating in tested mice. Thiamine and benfotiamine reduced GSK3b expression in the prefrontal cortex and the hippocampus that was more pronounced in the animals with low floating, in case of the measurements made in the prefrontal cortex. Together, these data suggest pro-cognitive and antidepressant-like effect of benfotiamine that are partly shared by thiamine and can be mediated by their inhibitory effect on the GSK3