Background: Global prescription drug use has been increasing continuously for decades. The gut microbiome, a key contributor to health status, can be altered by prescription drug use, as antibiotics have been repeatedly described to have both short-term and long-standing effects on the intestinal microbiome. Aim: To summarise current findings on non-antibiotic prescription-induced gut microbiome changes, focusing on the most frequently prescribed therapeutic drug categories. Methods: We conducted a systematic review by first searching in online databases for indexed articles and abstracts in accordance with PRISMA guidelines. Studies assessing the intestinal microbiome alterations associated with proton pump inhibitors (PPIs), metformin, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, statins and antipsychotics were included. We only included studies using culture-independent molecular techniques. Results: Proton pump inhibitors and antipsychotic medications are associated with a decrease in α diversity in the gut microbiome, whereas opioids were associated with an increase in α diversity. Metformin and NSAIDs were not associated with significant changes in α diversity. β diversity was found to be significantly altered with all drugs, except for NSAIDs. PPI use was linked to a decrease in Clotridiales and increase in Actinomycetales, Micrococcaceae and Streptococcaceae, which are changes previously implicated in dysbiosis and increased susceptibility to Clostridium difficile infection. Consistent results showed that PPIs, metformin, NSAIDs, opioids and antipsychotics were either associated with increases in members of class Gammaproteobacteria (including Enterobacter, Escherichia, Klebsiella and Citrobacter), or members of family Enterococcaceae, which are often pathogens isolated from bloodstream infections in critically ill patients. We also found that antipsychotic treatment, usually associated with an increase in body mass index, was marked by a decreased ratio of Bacteroidetes:Firmicutes in the gut microbiome, resembling trends seen in obese patients. Conclusions: Non-antibiotic prescription drugs have a notable impact on the overall architecture of the intestinal microbiome. Further explorations should seek to define biomarkers of dysbiosis induced by specific drugs, and potentially tailor live biotherapeutics to counter this drug-induced dysbiosis. Many other frequently prescribed drugs should also be investigated to better understand the link between these drugs, the microbiome and health status.