With the worldwide use of electronic cigarettes (e-cigarettes) as a substitution for tobacco, the effects of e-cigarette vapor exposure on human health have been investigated. However, the comparison of long-term effects of aerosol inhalation with combustible cigarette and e-cigarette on the psychiatric behaviors has not been fully revealed. The present study examines the distinct effects of combustible cigarette and e-cigarette on anxiety, depression, cognition, and social behaviors. Here we found that the combustible cigarette induced the higher level of anxiety after long-term inhalation compared to the e-cigarettes with or without the tobacco flavor. Since the mechanism of action on the psychiatric behaviors entails the alterations on the neuroimmune-sensors and principal regulators such as glial cells, we further profiled the alterations of microglia and astrocytes by chronic inhalation of combustible tobacco cigarette, specifically the negative correlations between the IBA-1 level in the locus coeruleus (LC) and the latency to nest in VLT; as well as the GFAP level in LC and the open arm time in EPM were observed. Our current data provided an insight into the less impact of e-cigarettes on the anxiety-like behaviors and neuroimmune activation compared to combustible tobacco cigarettes which is not related to the flavor in e-cigarette, and the modulation on the neuroimmune signals in LC could be a therapeutic target for smoking-related anxiety.