Bidirectional correlations between cigarette smoking and affective disorders, such as depression, anxiety, and schizophrenia, are well documented. These findings have led to substantial investigations into the effects of the major tobacco alkaloid, nicotine, and to a lesser extent, of other tobacco constituents, on the central nervous system (CNS). However, systematic profiling of the neuropharmacological effects of tobacco constituents is limited. To elucidate the effects of selected tobacco constituents on the CNS, we used the SmartCube® system, which captures and classifies behavioral features of compound-treated mice, to profile the psychiatric drugs-like properties of previously reported neuroactive tobacco compounds in mice. Daily intraperitoneal injection of nicotine (0.5 and 1 mg/kg/day) and anatabine (5 mg/kg/day) for 7 days produced antidepressant-like behavioral SmartCube® signatures in mice, and these results were supported by the improved active coping responses in the forced swim tests. Conversely, ferulic acid did not show any identifiable class signatures in the SmartCube® tests, but rather displayed subclass signatures associated with acetylcholinesterase inhibitors. In novel object recognition memory test in rats, ferulic acid improved memory after 7 days of subcutaneous injection at 0.3 or 3 mg/kg/day. These results support previous findings showing the antidepressant drug-like effects of nicotine and the nootropic effects of ferulic acid. This is also the first report on the antidepressant drug-like effects of anatabine in rodents. This study provides a systemic behavioral evaluation of tobacco alkaloids and further insights into the association between affective disorders and smoking incidence.