NMDA) receptor antagonists, and tricyclic antidepressants (TCAs), exhibit antibacterial activities. Hence, this systematic review explores the impact of antidepressants on gut microbiota and potential strategies to alleviate antidepressant-associated dysbiosis. Methods This systematic review was conducted based on the PRISMA guidelines. Predefined MeSH terms 'antidepressants AND gut microbiome'; 'antidepressants AND antimicrobial activity' were used in three databases (Pubmed, Embase, Pro-Quest; from database inception to June 2021). Studies reporting on the gut microbiota variation and antidepressants action were included. Studies without antidepressants and/or gut microbiome data were excluded, including conference proceedings, reviews, systematic reviews, meta-analyses, and commentaries. Results According to the study's inclusion criteria, twelve studies out of 300 articles were selected for the qualitative analysis. In the in-vivo studies, animals administrated with SSRIs had a decreased abundance of Firmicutes, Alphaproteobacteria, Bacteroides, Ruminococcus, Adlercreutzia, Turicibacter, and alpha diversity but an increase in Prevotella, Parabacteroides, Butyricimonas, and Alistipes. Besides, antidepressants were shown to exhibit significant in vitro antimicrobial activity against Akkermansia muciniphila, Bifidobacterium animalis, and Bacteroides fragilis, suggesting that the chronic use of antidepressants potentially causes adverse effects due to their antimicrobial effects and dysbiosis (IDDF2021-ABS-0164 Figure 1. Illustration of gut microbiota dysbiosis in response to antidepressants). Probiotics, prebiotics and fecal microbiota transplantation are shown to be promising strategies to ameliorate antidepressant-associated dysbiosis. Conclusions Understanding the interaction between antidepressants and gut microbiota, including dysbiosis as a consequence of treatment and potential side effects, is vital for the future development of better and personalized treatment. Supplementing the gut microbiome with prebiotics/probiotics could be an adjuvant treatment to improve the clinical efficacy of the current antidepressant therapies.