The global spread of microbial resistance coupled with high costs and slow pace in the discovery of a new antibiotic have made drug repositioning an attractive and promising alternative in the treatment of infections caused by multidrug resistant (MDR) microorganisms. The reuse involves the production of compounds with lower costs and development time, using diversified production technologies. The present systematic review aimed to present a selection of studies published in the last 20 years, which report the antimicrobial activity of non-antibiotic drugs that are candidates for repositioning, which could be used against the current microbial multidrug resistance. A search was performed in the PubMed, SciELO and Google Scholar databases using the following search strategies: [(drug repurposing) OR (drug repositioning) OR (repositioning) AND (non-antibiotic) AND (antibacterial activity) AND (antimicrobial activity)]. Overall, 112 articles were included, which explored the antimicrobial activity in antidepressants, antihypertensives, anti-inflammatories, antineoplastics, hypoglycemic agents, among other drugs. It was concluded that they have significant antimicrobial activity in vitro and in vivo, against standard strain and clinical isolates (Gram-negative and Gram-positive) and fungi. When associated with antibacterials, most of these drugs had their antibacterial activity enhanced. It was also a consensus of the studies included in this review that the presence of aromatic rings in the molecular structure contributes to antimicrobial activity. This review highlights the potential repositioning of several classes of non-antibiotic drugs as promising candidates for repositioning in the treatment of severe bacterial infections of MDR bacteria, extensively resistant (XDR) and pan-resistant (PDR) to drugs.