Antidepressants are among the most widely used neuropsychiatric drugs, yet their interactions with the gut microbiome remain mechanistically unresolved. Here, we synthesize evidence across microbial physiology, host metabolism, and in silico enzymatic predictions to delineate how selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs) interface with bacterial systems. Although direct experimental confirmation of antidepressant biotransformation is lacking, convergent signals — induction of efflux pump genes, enhanced plasmid transfer, neurotransmitter modulation, transporter interference, and broad-spectrum duloxetine bioaccumulation — reveal multiple pathways through which these compounds reshape microbial function. Integrative enzyme analyses further identify a putative digallate acylhydrolase capable of biotransforming fluoxetine, providing the first mechanistically plausible candidate for SSRI metabolism by gut bacteria. We additionally map antidepressant-associated shifts in host tryptophan metabolites and systemic LPS levels, and identify bacterial taxa with functional potential across the indole, serotonin, and kynurenine pathways. Together, this review provides a unified mechanistic framework for antidepressant-microbiome interactions and outlines testable hypotheses toward microbiome-informed antidepressant strategies.