<p>Bacterial vaginosis (BV) is the most commonly diagnosed vaginal infection in women of reproductive age, with most patients unaware that they have BV due to its asymptomatic nature. BV is a dysbiotic condition defined by a deviation from the healthy <i>Lactobacillus</i> dominance to a polymicrobial anaerobic bacterial community that increases the risk of sexually transmitted infections and adverse reproductive outcomes, including spontaneous preterm birth. The increasing number of infectious agents in BV, biofilm persistence and antibiotic resistance in the vaginal canal hinder effective treatments with antibiotics leading to consistent recurrence of BV in many women (30–70%). Like in the gut, these vaginal drug-microbiome interactions termed pharmacomicrobiomics could alter drug disposition, mechanism of action, and toxicity that reduce the efficacy of antibiotics and increase the risk of persistent and recurrent BV and its sequelae. For instance, both vaginal epithelial and bacterial cells co-exist and possess enzymes that metabolize antibiotics, and transporter proteins that expel drugs and toxins, rendering them ineffective. Despite significant progress on pharmacomicrobiomics in the gut, little is known about this phenomenon in the vaginal microenvironment, which harbors a consequential microbiota and a major source of infection and antibiotic resistance. Therefore, to improve therapeutic outcomes and reduce the rate of persistent/recurrent BV and infection-associated preterm birth, we present an overview of the evidence pertaining to the effect of vaginal microbiome-drug interactions and efficacy of antibiotics against recurrent BV. We also highlight plausible mechanistic underpinnings of these interactions and implications for treatment modalities to combat infection-associated preterm birth.</p>